Patient with Corticobasal Syndrome Showing Disease-Associated Biomarkers of Dementia with Lewy Bodies: A Treviso Dementia (TREDEM) Registry Case Report

Objective

We present a patient with CBS and mild cognitive impairment (MCI) who showed the presence of α-synuclein aggregates in the cerebrospinal fluid (CSF) and in the olfactory mucosa (OM) samples, and a quantitative electroencephalography (QEEG) pattern of early-stage dementia with Lewy bodies (DLB).

Case presentation

An 82-year-old right-handed man, a retired teacher, was referred to the Treviso Cognitive Impairment Center (TCIC) in September 2018, complaining of increasing motor impairments that had arisen three years before. He reported difficulties in moving his left arm and foot, tremor in his left hand and gestures of the left upper limb that appeared to be independent of his will, characteristic of anarchic hand phenomenon [12]. He also reported needing visual confirmation to be aware of the movement made by his left arm, suggesting the presence of alien limb phenomenon. A fall to the ground, which occurred a month earlier, due to probable failure of the left lower limb, was also reported.

The patient, with 17 years of education, worked as a teacher of Italian Literature. He drank a glass of wine a day and did not smoke. He suffered from malaria at a young age and reported a transient ischemic attack in 2003. No family history of neurodegenerative or psychiatric diseases was reported.

Upon physical examination, the patient was alert and cooperative. No apparent visual field deficits were detected; the pupils were isocyclic, isochoric; ocular movements were normal. No asymmetries of the face were detectable. The palatal velum was in axis and the tongue midlined and protrusible. The patient presented resting tremor, mild extrapyramidal hypertonus, mild bradykinesia on the left side, and severe apraxia on the left upper limb. The patient reported that the tremor in his left upper limb was accentuated by emotional tension, consequent to the awareness of his motor limitations. His sense of smell was preserved.

Osteo-tendon reflexes were prevalent on the left. Mild muscle strength deficit, 4/5 on the Medical Research Council Scale [15] and mild hypoesthesia were observed on the left side. The patient showed signs of apraxia on the left limbs. Eye movements were normal. Brain CT and MRI, performed in 2018 before the patient was referred to the TCIC, showed a posterior parietal (Figs. 1c, 1d, 2b, 2c) and temporal cortical atrophy (Fig. 1a) prevalent in the right hemisphere and a moderate atrophy of the precuneus (Figs. 1e, 2d) and frontal cortex (Figs. 1a, 1b, 2a).

Fig. 1

CT scan (February 17, 2018), with no contrast, showing a posterior parietal (1c, 1d) and temporal cortical atrophy (1a) prevalent on the right hemisphere and a moderate atrophy of the precuneus (1e) and frontal cortex (1a, 1b). The hippocampus and the mesial temporal area appeared fairly preserved.

Fig. 2

The first (March 3, 2018) and the second (December 14, 2019, not showed) structural MRI T1 and T2 weighted sequences reported a posterior parietal (2b, 2c), temporal (not shown) and frontal cortex (2a) atrophy prevalent on the right hemisphere and an atrophy of the precuneus (2d).

In November 2018, the patient underwent a ¹⁸F-FDG PET showing reduced glucose metabolism in the occipital, parietal, temporal, and lateral frontal cortices on the right side along with the involvement of the right supplementary motor area (Fig. 3a–3e), of the precuneus (Fig. 3f), and partially of the primary sensory-motor area.

Fig. 3

The first ¹⁸F-FDG PET study (November 13, 2018) is illustrated by the images above (3a-3e axial sections; 3f sagittal section) while the second study (December 6, 2019) produced the images below (3g–3k axial sections; 3l sagittal section). The first ¹⁸F-FDG PET study showed reduced glucose metabolism in the occipital, parietal, temporal, lateral frontal cortex on the right side along with the involvement of right supplementary motor area (3a–3e), of the precuneus (3e, 3f), and partially of the primary sensory-motor area. The hypometabolism of the precuneus on the right side suggested an initial sign of the posterior cingulate island on the right (3e). The right putamen was relatively less metabolically active (not shown). The left parietal and the temporal cortex were also moderately hypometabolic. The second study produced images substantially unchanged from the previous ones.

In December 2018 the patient performed a ¹²³I-ioflupane SPECT (DaT-SPECT) which showed a mild, albeit non-pathological at DaTQUANT (see methods), thinning of the posterior portion of the right putamen (Fig. 4). A first neuropsychological evaluation was carried out on September 27, 2018 and showed mild deficits in visual-perceptive memory (Table 1).

Fig. 4

The ¹²³I-ioflupane SPECT (DaT-SPECT), performed on December 20, 2018. It showed a mild thinning of the posterior portion of the right putamen that did not appear to be pathological in the semi-quantitative analysis (DaTQUANT). The second study (December 12, 2019, not shown) produced images and semi-quantitative analysis essentially unchanged.

In January 2019, the patient was clinically re-evaluated: pendolar movements of the left upper limb were reduced during walking. The left hand, after a few steps, assumed a dystonic posture with levitation. Rest tremor, plastic rigidity, and bradykinesia were prevalent on the left side.

The onset with memory deficits and atrophy and hypometabolism in right parieto-temporal cortical areas was diagnosed as MCI/prodromal Alzheimer’s disease (AD) presenting with CBS. Levodopa/Carbidopa 100/25 mg three times a day was initiated with minimal benefit on the rigidity. Participation in the walking and reading groups for people with MCI, organized by the TCIC, was proposed together with moderate but continuous physical activity, Mediterranean diet adherence, and socialization.

In August 2019 the patient was re-evaluated. He presented with a worsening of motor signs with instability in walking and loss of balance, resulting in frequent falls. He complained of difficulty in coordinating the two hands and signaled that his left upper limb was increasingly escaping his control. At physical examination, compared to the previous evaluations, there was an evident apraxia of the left hand during tasks that required synergistic coordination of both hands, e.g., buttoning a shirt or tying shoelaces.

In October 2019 the patient showed cautious and insecure walking with a tendency to lose balance. Standing was possible on a restricted basis but with a tendency to retropulsion. In addition to the ongoing therapy, the patient started a course of physiokinetic therapy. Further neuropsychological evaluations were carried out in 2019, respectively on February 6 (not shown in Table 1), May 16, August 1 (not shown in Table 1), and December 4, and showed overall mild memory deficit, constructive apraxia, and borderline executive functions (Table 1). The cognitive profile and the other clinical and instrumental elements still supported the diagnosis of MCI/prodromal AD presenting as CBS.

In November 2019, the patient was admitted to the emergency room for vasovagal syncope. Due to the physical deterioration found in October 2019, structural and metabolic imaging techniques were repeated. A brain MRI, performed on December 14, 2019 (not shown), a second ¹⁸F-FDG PET, and a further ¹²³I-ioflupane SPECT (DaT-SPECT, not shown) were substantially unchanged from the previous ones.

The patient was subsequently evaluated in January and in October 2020. The patient reported a worsening of his motor performance, in particular in concomitance and after the period of social restrictions related to the SARS-CoV2 pandemic. By October 2020, the situation had objectively worsened further. The patient presented hypomimia. Verbal fluency was intact but with monotone speech. The patient reported tactile hypoesthesia of the left side of the face. Changes in posture were performed with extreme uncertainty and with the examiner’s help. The patient showed precarious control of the trunk when sitting, with a tendency to retropulsion. In a standing position his balance was facilitated by placing his feet further apart. The patient was also supported by the examiner; Romberg’s test was positive. We observed freezing of gait, possible only with unilateral support by the examiner and constant search for support with the contralateral limb. While walking, the feet had to keep a certain distance, otherwise the left leg tended to hinder the step of the right leg.

The patient showed severe apraxia of the left upper limb in transitive and intransitive gestures, symbolic and imitative. Graphesthesia and spatial discrimination of the tactile stimulus were not clearly interpretable in relation to the patient’s responses. Astereognosis was present on the left upper limb. The left upper limb could not be kept extended forward. Plastic hypertonia of upper limbs (left > right), and paratonia to lower limbs were present along with neck rigidity. The patient reported tactile hypoesthesia on the left side. Plantar reflex was in flexion on the right, no response was found on the left. The index-nose test was correctly performed on the right, but not on the left.

Two new neuropsychological evaluations were carried out on February 2 (not shown in Table 1) and on October 6, 2020 (Table 1). The results showed short, long-term, and visuospatial memory loss, executive function deficits, apraxia on the left side, and apperceptive agnosia.

At the end of 2020 we concluded with a diagnosis of MCI/prodromal AD presenting as CBS. At that time, the patient’s therapy included Levodopa/Carbidopa 100/25 mg 1 tablet three times a day, Simvastatin 20 mg 1 tablet a day, Perindopril 4 mg 1 tablet a day, and Ticlopidine 250 mg 1 tablet a day.

Suspecting a possible evolution of MCI towards a disease in the spectrum of tauopathies, the determination of CSF markers for AD, including amyloid-β, tau, phospho-tau, was carried out. The presence of AD related protein level abnormalities was excluded. The determination of α-synuclein in CSF and in samples of the nasal mucosa were subsequently performed and a QEEG assessment was completed as well.

Alpha-synuclein aggregates were found in both CSF and in OM samples. Quantitative spectral analysis of the EEG showed a typical pattern of early stage DLB with the presence of a dominant pre-alpha band in posterior derivations.

The finding of α-synuclein deposits in two different tissues was surprising because CBS is usually associated with tauopathies. In 2021, the patient’s condition worsened further. He stopped walking independently. His mood became depressed and an antidepressant therapy with Escitalopram, 10 mg 1 tablet daily, was started.

The general conditions of the patient and his concomitant poor compliance did not allow ¹²³I-metaiodobenzylguanidine cardiac sympathetic imaging, which could have further clarified the DLB pathology. The patient’s general condition further deteriorated, with urinary incontinence, further reduced mobility and secondary difficulty in caring for him, until his death in February 2022.

Neuropsychological evaluations

Neuropsychological evaluations were carried out seven times (of these, four illustrated in Table 1) from admission in September 27, 2018 to October 6, 2020 (the last one performed at patient’s home, due to the worsening of his mobility). Psychometric test results are included in Table 1 (raw scores, corrected scores, and cut-offs). The z-score was also calculated. It is the raw score of the neuropsychological test minus the population mean, divided by the population standard deviation. Such normative data (mean and standard deviation) are provided by the authors of the respective neuropsychological tests.

The evaluation included the following tests: Clinical Dementia Rating [17], Mini-Mental State Examination [18], Digit Span [19], Visuo-Spatial Span [20], Short Story Memory Test [20], Rey-Auditory Verbal Learning Test [21], Rey-Osterrieth Complex Figure test [22], Attentive Matrices [20], Semantic and Phonemic Verbal Fluencies [20], Token Test [20], Drawing Copy Test [23], Ideational Apraxia [24], Ideomotor Apraxia [25], Buccofacial Apraxia [26], Poppelreuter-Ghent’s overlapping figures test [27], Clock Drawing Test [23], Cognitive Estimation Test [28], X-O-N- Warrington Test [29], and the Neuropsychiatric Inventory [30].

Structural and nuclear medicine imaging

The CT scans were acquired with an EMOTION 6 Siemens volumetric scanner. Section orientation was parallel to the orbitomeatal plane. Sections on the same plane (time of 2 s, 120 kV, 130 mA, section thickness of 5 mm, no intersection gap) covered the remaining brain from the inferior aspect of the cerebellum to the vertex of the cranium.

The structural MRI scan was performed with 3-T Magnetom 135 mT of gradients with 64 channels (Siemens Magnetom Vida). T1, T2, and T2 FLAIR weighted sequences were extracted.

The patient underwent an ¹⁸F-FDG PET brain scan using a PET tomograph Discovery MI (General Electric Healthcare). The CT scan was used for attenuation and scatter correction with set voltage tuned to 120 kV. The scan was obtained over 10 min, starting 60 min after i.v. injection of 227 MBq, and the images of the two scans were visually assessed.

Moreover, to obtain the DaT-SPECT images, the patient was administered two capsules of 200 mg of potassium perchlorate orally, approximately 1 h before the injection of ¹²³I-ioflupane. The patient was administered 170 MBq of ¹²³I-ioflupane intravenously, and SPECT imaging was detected 3 h post-injection. Furthermore, a DaTQUANT analysis, an adjunct processing tool with advanced quantitative uptake methods and a designated normals database, for a more accurate assessment of a patient’s case, was also performed [31, 32].

An amyloid PET was not performed given the patient’s advanced age at first evaluation at our center. Indeed, the prevalence of amyloid PET positivity among healthy older adults increases exponentially with age and, in particular, is more than 50% in persons aged 80–90 years [33].

Quantitative electroencephalography

EEG and QEEG assessments were performed with nineteen Ag/AgCl disk scalp electrodes, placed according to the international 10–20 system, recorded EEG from Fp1, Fp2, Fz, F3, F4, F7, F8, Cz, C3, C4, Pz, P3, P4, T3, T4, T5, T6, O1, and O2. EEG activity was analyzed from single or multiple leads grouped to define the following scalp regions: anterior (Fz, Fp2, F7, Fp1, F3, F4, F8), central (Cz, C3, C4), posterior (Pz, P3, P4, O1, O2), temporal (T3, T4, T5, T6), peripheral (Fp1, Fp2, F8, T4, T6, O1, O2, T3, T5, Fz), and internal (F3, F4, Fz, C3, Cz, C4, P3, Pz, P4). Recordings were obtained with the patient resting comfortably, with eyes closed. Patient’s wakefulness was ascertained every about 2 min inviting him to open his eyes and checking block reactions. Electrodes to record electrocardiogram were also applied. EEG was acquired as a continuous signal for 20 min and visually inspected for current clinical interpretation or detection of artefacts and stored in order to be epoched in off-analysis setting as series of 2 s-long epochs. Two electrodes from posterior derivations (O1, O2) were considered for the analysis.

Ninety blocks of artefact-free 2-s-long epochs appearing consecutively were selected off-line by visual inspection. Fast Fourier transform was applied on each epoch allowing a frequency resolution of 0.5 Hz. The obtained spectra values were then processed in order to compute a mean Power Spectrum for each channel and divided automatically into 4 frequency bands: 3–4 Hz (delta), 4.5–5.5 Hz (theta), 6–7.5 Hz (pre-alpha), and 8–12 Hz (alpha) [34]. EEG traces were quantified by the following mathematical descriptors: DF, i.e., the frequency where the spectral power value was greatest, was evaluated for each epoch; DFV expressing the variability of DF across the 90 analyzed epochs; FP, i.e., percent of epochs where a dominant frequency band was observed (1–100%) in order to define the compressed spectral array pattern of the recording, according to Bonanni [34].

Cerebrospinal fluid analyses

CSF Aβ₄₂, total Tau (tTau), and phosphorylated Tau (pTau181) levels were determined by using commercially available INNOTEST ELISA kit (Fujirebio Europe N.V., Ghent, Belgium), as previously described [35]. CSF Aβ₄₂, tTau, and pTau181 levels were checked in duplicate. Pathological values orienting toward an AD pathology were assumed for total Tau >350 pg/mL and Aβ₄₂/pTau181 ratio <7 [35]. Alpha-synuclein RT-QuIC assay was performed as previously described [36].

Olfactory brushing and α-synuclein RT-QuIC analysis

An otolaryngologist visualized the nasal cavity using a 0° endoscope. Four OM samples were collected through the middle turbinate using flocked swabs (COPAN Italia, Technologies) and OM samples were processed for RT-QuIC analysis. Alpha-synuclein RT-QuIC assay in OM and CSF samples was performed as previously reported in patients with Parkinson’s disease, DLB, and isolated REM sleep behavior disorder [37, 38].

Neuropsychological evaluation

Seven neuropsychological assessments were conducted between September 27, 2018 and October 6, 2020; for the sake of brevity, only the four most significant of these are illustrated in Table 1. The neuropsychological evaluations carried out were numerous because four of these were part of TCIC protocol for the prevention of cognitive deterioration for people with MCI [39, 40], in which the patient was included. The patient always came to the clinical interviews accompanied by his wife. The last evaluation took place at the patient’s house because of his severe disability at that time.

During the first evaluation, the patient showed an isolated deficit of the visuo-spatial memory domain. In the second evaluation (February 6, 2019; not shown) the patient performed poorly on the Drawing Copy Test and on immediate recall as measured by the Rey-Auditory Verbal Learning Test.

The third evaluation (May 16, 2019; Table 1) showed a deficit in memory (Short Story Test) and borderline executive functions (Clock Drawing Test). The fourth evaluation (August 1, 2019; not shown) did not show significant changes compared to the previous ones.

The fifth evaluation (December 4, 2019; Table 1) showed memory deficits (delayed recall, Rey-Auditory Verbal Learning Test, and Visuo-Spatial Span with borderline score) and constructional apraxia (Drawing Copy Test).

The sixth evaluation (February 2, 2020; not shown) did not show significant changes compared to the previous one. The last evaluation (October 6, 2020) showed memory deficits (Immediate and Delayed Recall Rey-Auditory Verbal Learning Test; Visuo-Spatial Span; Short-Story Memory Test), executive deficits (Clock Drawing Test) and severe apperceptive agnosia (X-O-N Warrington and Taylor test) and ideomotor apraxia on the left side.

Structural and nuclear medicine imaging

The CT scans (February 17, 2018) showed a posterior parietal cortical atrophy prevalent on the right hemisphere (Fig. 1c, 1d), atrophy of the precuneus area (Fig. 1e), of the temporal and of frontal cortex (Fig. 1a, 1b). The hippocampus and the mesial temporal area appeared fairly preserved.

The first (March 3, 2018) and the second (December 14, 2019, not showed) structural MRI T1 and T2 weighted sequences reported a posterior parietal (Fig. 2b, 2c), temporal (not shown) and frontal cortex (Fig. 2a) atrophy prevalent on the right hemisphere and an atrophy of the precuneus (Fig. 2)d.

The first ¹⁸F-FDG PET study (November 13, 2018) showed reduced glucose metabolism in the occipital, parietal, temporal, and lateral frontal cortex on the right side along with the involvement of right supplementary motor area (Fig. 3a–3e), of the precuneus (Fig. 3e, 3f), and partially of the primary sensory-motor area. The hypometabolism of the precuneus on the right suggested the sign of the posterior cingulate island on the right (Fig. 3e). The right putamen was relatively less metabolically active (not shown). The left parietal and the temporal cortex were also moderately hypometabolic. The second study (December 6, 2019) produced images substantially unchanged from the previous ones.

The ¹²³I-ioflupane SPECT (DaT-SPECT), performed on December 20, 2018, showed a mild reduced uptake of the posterior portion of the right putamen that did not appear to be pathological in the semi-quantitative analysis (DaTQUANT). The second study (December 12, 2019, not shown) produced images and semi-quantitative analysis that were essentially unchanged.

Cerebrospinal fluid analysis

The CSF analysis revealed a Aβ₄₂ level of 403 pg/ml, t-tau of 395 pg/ml, p-tau 181 of 59 pg/ml, and Aβ₄₂ to p-tau 181 ratio of 6.8.

AD biomarker assays were not clearly pathological. RT-QuIC for α-synuclein in CSF was positive.

Olfactory mucosa brushing analysis

RT-QuIC for α-synuclein in olfactory mucosa samples was positive.

Quantitative electroencephalography

The spectral analysis showed a dominant frequency varying between 6 and 10 Hzs in the posterior derivations, a supportive biomarker of DLB diagnosis [41].

Conclusions

We discussed the case of a patient who showed a CBS clinical phenotype and α-synuclein deposits in CSF and OM samples together with one core clinical feature and potential biomarkers for the research diagnostic criteria of possible MCI-LB.

The clinical case presented is in addition to the very few examples of CBS with biological evidence of LB pathology already described in the literature.