Pick's Disease Presenting as Tremulous Parkinsonism with Limited Levodopa Response—A Rare Cause of Corticobasal Syndrome

Abstract

Background

Corticobasal syndrome is a clinical diagnosis and common pathological causes are corticobasal degeneration, progressive supranuclear palsy and Alzheimer's disease.

Objectives

We would like to highlight a rare but important differential of corticobasal syndrome.

Methods

A 78‐year‐old female had a 4‐year history of predominantly right‐hand rest tremor, worsening of handwriting but no change in cognition. The clinical examination showed right upper limb postural and kinetic tremor, mild wrist rigidity and reduced amplitude of right‐sided finger tapping. She was initially diagnosed as idiopathic Parkinson's disease. Five years after onset of symptoms, she demonstrated bilateral myoclonic jerks and right upper limb dystonic posturing. She could not copy movements with the right hand. The magnetic resonance imaging (MRI) revealed disproportionate atrophy in the parietal lobes bilaterally. The clinical diagnosis was changed to probable corticobasal syndrome. She passed away 11 years from onset of symptoms at the age of 85 years. She underwent a post‐mortem.

Results

The anterior and posterior frontal cortex, anterior cingulate, temporal neocortex, hippocampus and amygdaloid complex demonstrated considerable tau‐related pathology consisting of a dense background of neuropil threads, and rounded, paranuclear neuronal inclusions consistent with Pick bodies. The immunostaining for three microtubule binding domain repeats (3R) tau performed on sections from the frontal and temporal lobes, basal ganglia and midbrain highlighted several inclusions whilst no 4R tau was observed. She was finally diagnosed with Pick's disease.

Conclusions

Pick's disease can rarely present with clinical features of corticobasal syndrome.

Case Report

A 78‐year‐old female presented with a 4‐year history of predominantly right‐hand rest tremor. Her handwriting had become progressively smaller, and she reported impaired right‐hand dexterity and stiffness over the preceding 12 months, with difficulty handling utensils and buttoning clothes. She reported no falls, unsteadiness or freezing when walking. Bladder and bowel functions, speech and swallowing were normal. She had no dream enactment behavior during sleep. Her daughter noticed no change in cognition, mood, behavior, or any hallucinations. Her medical history included diabetes mellitus type II and hypertension, treated with metformin and bendroflumethiazide. She had no family history of early‐onset dementia or parkinsonism.

Examination revealed a right upper limb postural and kinetic tremor. There was mild right wrist rigidity and reduced amplitude of right‐sided finger tapping. The deep tendon reflexes were symmetrical and plantar responses were flexor. She was initially diagnosed with probable idiopathic Parkinson's disease and was started on levodopa but reported no response to co‐beneldopa 100/25 mg three times daily, with worsening impairment of upper limb function, struggling with daily activities like using cutlery, brushing teeth and dressing. She also reported worsening jerky movements of upper limbs, with levitation of the right arm and a feeling that the right arm was not part of her and had a will of its own, although there were no complex unintentional behaviors or intermanual conflict. The follow‐up examination 1 year later (5 years after onset) demonstrated myoclonic jerks (right more than left) worsened by action, and right upper limb dystonic posturing. There was no clear sequence effect on finger tapping but she was unable to perform the movement, particularly with the right hand. There was asymmetric right greater than left bilateral upper limb rigidity with ideomotor apraxia of the upper limbs (Video 1).

Video 1.

Video showing asymmetric right>left dystonic posturing with apraxia while following commands, non‐representational hand postures and mimicking actions. Body part substitution is shown on doing the latter actions. Upper limb myoclonic jerks on posture holding and goal directed movement are seen.

Magnetic resonance imaging (MRI) revealed generalized widening of the sulci and ventricles in keeping with a degree of mild atrophy and additional more advanced atrophy in the parietal lobes bilaterally which was worse on the left (Fig. 1A,B). No selective advanced temporal atrophy was noted. Few foci of high T2 signal in the white matter with slight prominence of the perivascular spaces in the basal ganglia was also noted which was attributed to possible early small vessel disease changes (Fig. 1C,D). The clinical diagnosis was revised to probable corticobasal syndrome (CBS) as per the current diagnostic criteria. ¹

Figure 1.

Axial T2 (A) and coronal fluid attenuated inversion recovery (FLAIR) (B) sequences demonstrating advanced parietal atrophy, prominent sulci (left>right) (arrowheads). Axial T2 (C) and coronal FLAIR (D) showing mild small vessel disease, prominent perivascular spaces and high T2 signal (arrows).

Her condition progressed slowly with worsening limb apraxia although she remained largely independent 7 years after onset, without cognitive or behavioral disturbance. In the following 2 years her condition deteriorated with worsening mobility, reduced speech and cognitive decline and she was admitted to a care home. She died at the age of 85 years, 11 years from onset.

Pathological Finding

The brain weighed 1035 grams. External examination revealed mild to moderate widening of sulci. Coronal slices showed dilatation of the lateral ventricles. Substantia nigra and coeruleus complex showed normal pigmentation for the age of this subject.

Microscopic examination demonstrated neuronal loss, reactive gliosis and micro‐vacuolization of the neocortical gray matter and allocortex, accompanied by white matter gliosis and axonal loss. The anterior cingulate gyrus, amygdala and hippocampus were the most severely affected regions and the visual cortex the less involved. The basal ganglia showed widespread gliosis and mild small vessel disease. The midbrain was gliotic with preservation of pigmented neurons in the substantia nigra. Pons, medulla, and upper cervical spinal cord showed mild reactive gliosis.

Anterior and posterior frontal cortex, anterior cingulate, temporal neocortex, hippocampus and amygdaloid complex demonstrated considerable tau‐related pathology consisting of a dense background of neuropil threads, and rounded, paranuclear neuronal inclusions consistent with Pick bodies, fewer globoid neurofibrillary tangles, a few pre‐tangles, and astrocytic plaques. Negligible tau accumulation was seen in the primary visual cortex. The allocortex was the most severely affected structure with the highest density of Pick bodies in the dentate gyrus. Oligodendrocytes with coiled bodies and white matter threads were also seen in the section from hippocampus. Tau accumulation was minimal in the occipital cortex. A few Pick bodies were seen in the globus pallidus. A few globoid tangles and threads were present in the substantia nigra, oculomotor nucleus and reticular substance of the midbrain, locus coeruleus and pontine nuclei, and rostral medulla. The cerebellum was spared.

The immunostain for three microtubule binding domain repeats (3R) tau performed on sections from the frontal and temporal lobes, basal ganglia and midbrain highlighted several inclusions (Fig. 2) whilst no 4R tau was observed.

Figure 2.

Dentate gyrus in endfolium shows Pick's bodies (A–immunoperoxidase, phosphorylated tau); Pick's bodies contain 3R tau (B, immunoperoxidase); Pick's bodies in the basal ganglia; whole mount sections stained with Luxol‐fast blue/Periodic Acid‐Schiff (PAS) (C) and for phosphorylated tau (D) (*putamen; **external segment of globus pallidus; ***posterior limb of external capsule; the arrow indicates the anterior commissure) (E–inset as indicated in Fig. (D), immunoperoxidase, phosphorylated tau).

Amyloid beta peptide pathology was observed in the neocortex, entorhinal cortex, and basal ganglia and consisted of diffuse plaques, linear subpial deposits, compact neuritic and cored plaques in keeping with Thal phase 3 and CERAD C2. Blood vessels were spared. Alpha‐synuclein and TAR DNA‐binding protein 43 (TDP43) staining did not show abnormal deposits. The features were consistent with stage III Pick's disease (PiD).

Discussion

We have documented a patient with PiD who presented with asymmetric parkinsonism with subsequent clinical features of CBS. We did not identify any clinical features suggesting an alternative diagnosis in our case, given the predominant motor presentation and lack of cognitive or behavioral disturbance. ² The initial diagnosis of iPD was discounted due to limited levodopa response, and clinical signs such as apraxia, alien limb phenomena and the lack of a clear sequence effect ie, the progressive decrement of amplitude and frequency of finger tapping, an essential feature of bradykinesia required for a diagnosis of iPD. The latter features would not be expected to respond to higher doses of levodopa, although we accept that this was not formally tested.

Our case indicates that PiD is a potential pathological substrate for CBS, even without typical early cognitive‐behavioral changes. PiD is part of the spectrum of frontotemporal lobar degeneration (FTLD). It generally presents either as behavioral variant frontotemporal dementia (bvFTD) or non‐fluent/agrammatic primary progressive aphasia (nfvPPA), with a peak age of onset in the sixth decade of life. ³ , ⁴ Accumulation of 3R tau in spherical neuronal inclusions (Pick bodies) and ballooned neurons (Pick cells) are the hallmark of the condition. ⁵ In contrast, the common causes of CBS include 4R tauopathies such as corticobasal degeneration and progressive supranuclear palsy, and Alzheimer's disease. ⁶ , ⁷

Corticobasal syndrome has previously been reported as an uncommon presentation of PiD. Whitwell and colleagues reported one out of 17 autopsy‐confirmed PiD was clinically diagnosed with CBS. ³ In clinicopathological studies of patients with CBS, PiD was identified infrequently: none of 16 patients in a UK cohort, ² and 1/40 and 1/13 in two cohorts from the US. ⁶ , ⁸ Lang and colleagues reported an autopsy‐proven asymmetric parietal PiD in a patient who was diagnosed with apraxia, parkinsonism, and myoclonus. ⁹ A recent study reported a 76‐year‐old man with speech apraxia, limb rigidity and apraxia, and apathy who was clinically diagnosed as CBS but post‐mortem revealed PiD. ¹⁰ Doran and colleagues reported a 57‐year‐old man who presented with CBS and nfvPPA, with normal structural brain imaging but reduced left frontotemporal perfusion on SPECT. Post‐mortem confirmed PiD. ¹¹ Both these patients had significant early cognitive impairment including executive dysfunction and disinhibition unlike our patient. Irwin and colleagues reported 21 cases of PiD; two patients had a presenting syndrome of CBS, but significant cognitive and behavioral features were apparent at presentation, with one showing features of bvFTD and one fulfilled criteria for nfvPPA. ¹² A recent large consortium‐based study of 338 patients with pathologically‐confirmed PiD reported CBS as a presenting feature in 15 cases (4.4%). ¹³ Therefore, in larger datasets CBS appears to be a more frequent presentation of PiD than smaller single‐center series had hitherto indicated.

Neuroimaging in our patient documented asymmetric frontal and posterior cortical atrophy, typically seen in patients with CBS. ⁶ MR imaging findings in PiD described predominant involvement of the amygdala, temporal pole, inferior temporal gyrus, and orbitofrontal cortex in those presenting with bvFTD, and left inferior frontal cortex and temporal lobe atrophy in nfvPPA. ³ However, these patterns evolved to a more posterior involvement in both groups. A recent case report of CBS‐PiD also showed relative sparing of temporal lobes, but severe frontoparietal atrophy. ¹⁰ In a subset of five PiD patients, Irwin and colleagues reported early atrophy in limbic, orbitofrontal and middle frontal regions with relatively less posterior involvement; however, CBS patients were infrequently seen in this series. ¹²

This case exemplifies the importance of ongoing assessment for red flags in individuals with a diagnosis of iPD; the lack of clear sequence effect of bradykinesia, limited levodopa response and the presence of apraxia were key to establishing a clinical diagnosis of CBS. The limited ability of clinical and radiological features to predict the underlying pathology of CBS is also illustrated here. The development of more specific biological measures such as seed amplification assays, now in development for tauopathies, could help with both clinical diagnosis and ensuring appropriate recruitment to mechanism‐based clinical trials. ¹⁴ PiD should be considered as a potential underlying pathological substrate for CBS, even in the absence of clear early cognitive‐behavioral features.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2)Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

S.B.: 1A, 1B, 1C, 2A, 2B

W.S.: 1C, 2B

I.D.: 1B, 1C, 2B.

Y.S.D.: 1C, 2B

J.M.: 1C, 2B

A.C.R.: 1B, 1C, 2B

F.R.: 1B, 1C, 2A, 2B

C.K.: 1A, 1B, 1C, 2A, 2B

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. Informed patient consent was obtained for the publication of the video. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Source and Conflicts of Interest: No specific funding was received for this work and the authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.