European Journal of Neurology 2014, 21: e56–e57
doi:10.1111/ene.12445
LETTER TO THE EDITOR In vivo decreased dopamine transporter uptake in corticobasal degeneration presenting with primary progressive aphasia without parkinsonism S. Gil-Navarroa, E. Gelpib, F. Lome~ nac, N. Montaguta, A. Llad oa,d, J. L. Molinuevoa,d and R. S anchez-Vallea,d a Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clınic, Barcelona; bNeurological Tissue Bank of the Biobank, Hospital Clinic, IDIBAPS, Barcelona; cNuclear Medicine Department, Hospital Clınic, Barcelona; and dInstitut d’Investigaci o Biom edica August Pi I Sunyer (IDIBAPS) Barcelona, Spain
Correspondence: R. Sanchez-Valle, Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clınic de Barcelona, c/Villarroel 170, 08036 Barcelona, Spain (tel.: (+34) 93 227 5785; fax: (+34) 93 227 5783; e-mail: [email protected]).
Keywords: 123I-FP-CIT SPECT, corticobasal degeneration, primary progressive aphasia, primary progressive nonfluent aphasia, tauopathy Received: 22 January 2014 Accepted: 12 March 2014 Recently, our group described that patients with the non-fluent/agrammatical variant of primary progressive aphasia (nfvPPA), especially those with negative Alzheimer’s disease (AD) biomarkers, presented decreased 123I-2bcarbomethoxy-3b-(4-iodophenyl)-N-(3fluoropropyl)-nortropane (123I-FP-CIT) uptake, even without clinical parkinsonism. This was not the case of other primary progressive aphasia (PPA) patients [1]. Our finding suggested subclinical nigrostriatal degeneration in nfvPPA patients that we related to frontotemporal lobar degeneration tau pathology (FTLD-tau). However, the study lacked neuropathological confirmation. Here, we present one nfvPPA patient from that study who showed in vivo decreased striatal 123I-FP-CIT uptake despite not having developed clinical parkinsonism. A tauopathy, with the neuropathological features of a corticobasal degeneration (CBD), was found in his postmortem study.
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Case report A 59-year-old right-handed man presented with a 1-year history of subtle verb conjugation difficulties. He had no other cognitive symptoms and no family history of dementia. His spontaneous speech was normal except for mild agrammatism (e.g. ‘Tomorrow we went to. . .’, ‘I reads a lot’). No grammatical errors were found on the writing description of a picture. He scored normal on the Boston Naming Test and fluency tests. The evaluation revealed spared object recognition and single-word comprehension but mild difficulties in sentence repetition. His neurological examination was entirely normal without evidence of dysarthria, non-verbal oral apraxia (NVOA) or apraxia of speech (AOS). MRI and 99m Tc-HMPAO SPECT scans showed atrophy and hypoperfusion of the left inferior frontal-insular region respectively. The cerebrospinal fluid (CSF) study showed normal levels of AD biomarkers (Ab1–42 725 pg/ml, total tau 319 pg/ml and phosphorylated tau 54 pg/ml). Serum progranulin levels were also normal. Visual examination of 123I-FP-CITSPECT (performed 18 months from symptom onset) showed mild reduced tracer uptake in the left striatum. A later 123I-FP-CIT-SPECT study (+3 years from onset) continued showing reduced left putaminal tracer uptake. Quantitatively, the striatal-tooccipital cortex uptake ratios for the left putamen and striatum were 2.16 and 2.05 initially and 1.91 and 1.72 on the second study, more than 1.5 SD lower than the same ratios in controls (2.58 0.22, 2.37 0.20 respectively) [1]. At the second 123I-FP-CIT-SPECT agrammatism was marked on spontaneous language and in writing. Clinical assessment showed simple phrases with omissions of grammatical morphemes [e.g. ‘I am (off) work’, ‘Today (is) Friday and (tomorrow is) the Saturday’]. There were no signs of dysarthria, NVOA, AOS or parkinsonism. Progressively, the patient developed severe behavioral symptoms (disinhibition, compulsions, aggressive behaviors) that needed treatment with atypical antipsychotics and non-cholinergic antidepressive drugs. When last seen, 5 years from onset, he was almost mute and severely demented but continued showing no
clear parkinsonian features. He died aged 64, after 5 years of disease duration. His brain autopsy showed mild frontal and marked temporal atrophy. Histologically, mild neuronal loss was present in the frontotemporal regions, basal ganglia and thalamus, with gliosis and superficial microvacuolation (Fig. 1a). A few ballooned neurons were observed in the frontal cortex and cingulum (Fig. 1b). There was mild loss of pigmented neurons of substantia nigra pars compacta and locus coeruleus. Immunohistochemistry revealed widespread neuronal and glial tau pathology, dominated by 4R-tau isoforms. Neuronal pathology included frequent pretangles in cortical areas, basal ganglia, thalamic nuclei, brainstem nuclei including substantia nigra, and dentate nucleus. Glial pathology was characterized by abundant tau (AT8) immunoreactive astrocytic plaques (Fig. 1c, e). Many oligodendrocytes contained cytoplasmic inclusions in the form of coiled bodies (Fig. 1d). The neuropathological diagnosis was 4R FTLD-tau, with characteristic features of CBD. Discussion Our patient’s primarily grammatical impairment with spared object knowledge and single-word comprehension was consistent with nfvPPA [2]. NfvPPA is commonly caused by FTLD with abnormal inclusions of 4R-tau isoforms in neurons and glia. Other less frequent pathologies, particularly AD and FTLD-TDP43, are also found [3]. This pathological heterogeneity calls for the study of specific in vivo biomarkers in PPA. The presence of AOS and atypical parkinsonian syndromes in PPA patients was highly indicative of underlying tau pathology in previous clinicopathological studies [3]. However, our patient had neither AOS nor parkinsonism. The study of CSF-AD biomarkers ruled out AD pathology. Likewise, serum progranulin levels ruled out underlying TDP43 pathology linked to GRN mutations. The patient’s serial 123I-FP-CITSPECT findings suggested nigrostriatal terminal dysfunction. 123I-FP-CITSPECT is abnormal in neurodegenerative parkinsonisms where there is loss of nigrostriatal nerve terminals and it also identifies the at-risk population
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
Letter to the Editor
Figure 1 (a) Mild frontal superficial spongiosis. (b) Hematoxylin and eosin stain: a few ballooned neurons with large cytoplasma and excentric nucleus in the frontal cortex and cingulum. (c), (d) AT8 immunohistochemistry: (c) tau-positive cortical astrocytic plaques and (d) taupositive white matter processes and coiled bodies. (e) RD4 immunohistochemistry: tau pathology immunoreactive for 4Rtau isoforms but not for 3R-tau isoforms. (f) RD3 immunohistochemistry.
for developing parkinsonism [1]. A previous clinico-pathological study found that the motor features of a corticobasal syndrome developed 4.1 years (2.1) after PPA onset [4]. Our patient did not develop clinical parkinsonism after 5 years from onset; however, 123I-FP-CIT-SPECT identified in vivo subclinical nigrostriatal degeneration which was related to CBD neuropathology. This clinicopathological study highlights that 123I-FP-CIT-SPECT could be a potential biomarker to identify PPA patients with underlying nigrostriatal degeneration associated with 4R FTLDtau pathology.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
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Acknowledgements
References
We are indebted to the Neurological Tissue Bank of the Biobanc-Hospital ClinicIDIBAPS for neuropathological studies and to brain donors for generous donations. This study was partially supported by GE Healthcare BioSciences S.A.
1. Gil-Navarro S, Lome~ na F, Cot A, et al. Decreased striatal dopamine transporter uptake in progressive non-fluent aphasia. Eur J Neurol 2013; 20: 1459–e126. 2. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006–1014. 3. Josephs KA, Duffy JR, Strand EA, et al. Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 2006; 129: 1385–1398. 4. McMonagle P, Blair M, Kertesz A. Corticobasal degeneration and progressive aphasia. Neurology 2006; 67: 1444– 1451.
Patient consent Obtained. Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
doi:10.1111/ene.12445
LETTER TO THE EDITOR In vivo decreased dopamine transporter uptake in corticobasal degeneration presenting with primary progressive aphasia without parkinsonism S. Gil-Navarroa, E. Gelpib, F. Lome~ nac, N. Montaguta, A. Llad oa,d, J. L. Molinuevoa,d and R. S anchez-Vallea,d a Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clınic, Barcelona; bNeurological Tissue Bank of the Biobank, Hospital Clinic, IDIBAPS, Barcelona; cNuclear Medicine Department, Hospital Clınic, Barcelona; and dInstitut d’Investigaci o Biom edica August Pi I Sunyer (IDIBAPS) Barcelona, Spain
Correspondence: R. Sanchez-Valle, Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clınic de Barcelona, c/Villarroel 170, 08036 Barcelona, Spain (tel.: (+34) 93 227 5785; fax: (+34) 93 227 5783; e-mail: [email protected]).
Keywords: 123I-FP-CIT SPECT, corticobasal degeneration, primary progressive aphasia, primary progressive nonfluent aphasia, tauopathy Received: 22 January 2014 Accepted: 12 March 2014 Recently, our group described that patients with the non-fluent/agrammatical variant of primary progressive aphasia (nfvPPA), especially those with negative Alzheimer’s disease (AD) biomarkers, presented decreased 123I-2bcarbomethoxy-3b-(4-iodophenyl)-N-(3fluoropropyl)-nortropane (123I-FP-CIT) uptake, even without clinical parkinsonism. This was not the case of other primary progressive aphasia (PPA) patients [1]. Our finding suggested subclinical nigrostriatal degeneration in nfvPPA patients that we related to frontotemporal lobar degeneration tau pathology (FTLD-tau). However, the study lacked neuropathological confirmation. Here, we present one nfvPPA patient from that study who showed in vivo decreased striatal 123I-FP-CIT uptake despite not having developed clinical parkinsonism. A tauopathy, with the neuropathological features of a corticobasal degeneration (CBD), was found in his postmortem study.
e56
Case report A 59-year-old right-handed man presented with a 1-year history of subtle verb conjugation difficulties. He had no other cognitive symptoms and no family history of dementia. His spontaneous speech was normal except for mild agrammatism (e.g. ‘Tomorrow we went to. . .’, ‘I reads a lot’). No grammatical errors were found on the writing description of a picture. He scored normal on the Boston Naming Test and fluency tests. The evaluation revealed spared object recognition and single-word comprehension but mild difficulties in sentence repetition. His neurological examination was entirely normal without evidence of dysarthria, non-verbal oral apraxia (NVOA) or apraxia of speech (AOS). MRI and 99m Tc-HMPAO SPECT scans showed atrophy and hypoperfusion of the left inferior frontal-insular region respectively. The cerebrospinal fluid (CSF) study showed normal levels of AD biomarkers (Ab1–42 725 pg/ml, total tau 319 pg/ml and phosphorylated tau 54 pg/ml). Serum progranulin levels were also normal. Visual examination of 123I-FP-CITSPECT (performed 18 months from symptom onset) showed mild reduced tracer uptake in the left striatum. A later 123I-FP-CIT-SPECT study (+3 years from onset) continued showing reduced left putaminal tracer uptake. Quantitatively, the striatal-tooccipital cortex uptake ratios for the left putamen and striatum were 2.16 and 2.05 initially and 1.91 and 1.72 on the second study, more than 1.5 SD lower than the same ratios in controls (2.58 0.22, 2.37 0.20 respectively) [1]. At the second 123I-FP-CIT-SPECT agrammatism was marked on spontaneous language and in writing. Clinical assessment showed simple phrases with omissions of grammatical morphemes [e.g. ‘I am (off) work’, ‘Today (is) Friday and (tomorrow is) the Saturday’]. There were no signs of dysarthria, NVOA, AOS or parkinsonism. Progressively, the patient developed severe behavioral symptoms (disinhibition, compulsions, aggressive behaviors) that needed treatment with atypical antipsychotics and non-cholinergic antidepressive drugs. When last seen, 5 years from onset, he was almost mute and severely demented but continued showing no
clear parkinsonian features. He died aged 64, after 5 years of disease duration. His brain autopsy showed mild frontal and marked temporal atrophy. Histologically, mild neuronal loss was present in the frontotemporal regions, basal ganglia and thalamus, with gliosis and superficial microvacuolation (Fig. 1a). A few ballooned neurons were observed in the frontal cortex and cingulum (Fig. 1b). There was mild loss of pigmented neurons of substantia nigra pars compacta and locus coeruleus. Immunohistochemistry revealed widespread neuronal and glial tau pathology, dominated by 4R-tau isoforms. Neuronal pathology included frequent pretangles in cortical areas, basal ganglia, thalamic nuclei, brainstem nuclei including substantia nigra, and dentate nucleus. Glial pathology was characterized by abundant tau (AT8) immunoreactive astrocytic plaques (Fig. 1c, e). Many oligodendrocytes contained cytoplasmic inclusions in the form of coiled bodies (Fig. 1d). The neuropathological diagnosis was 4R FTLD-tau, with characteristic features of CBD. Discussion Our patient’s primarily grammatical impairment with spared object knowledge and single-word comprehension was consistent with nfvPPA [2]. NfvPPA is commonly caused by FTLD with abnormal inclusions of 4R-tau isoforms in neurons and glia. Other less frequent pathologies, particularly AD and FTLD-TDP43, are also found [3]. This pathological heterogeneity calls for the study of specific in vivo biomarkers in PPA. The presence of AOS and atypical parkinsonian syndromes in PPA patients was highly indicative of underlying tau pathology in previous clinicopathological studies [3]. However, our patient had neither AOS nor parkinsonism. The study of CSF-AD biomarkers ruled out AD pathology. Likewise, serum progranulin levels ruled out underlying TDP43 pathology linked to GRN mutations. The patient’s serial 123I-FP-CITSPECT findings suggested nigrostriatal terminal dysfunction. 123I-FP-CITSPECT is abnormal in neurodegenerative parkinsonisms where there is loss of nigrostriatal nerve terminals and it also identifies the at-risk population
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
Letter to the Editor
Figure 1 (a) Mild frontal superficial spongiosis. (b) Hematoxylin and eosin stain: a few ballooned neurons with large cytoplasma and excentric nucleus in the frontal cortex and cingulum. (c), (d) AT8 immunohistochemistry: (c) tau-positive cortical astrocytic plaques and (d) taupositive white matter processes and coiled bodies. (e) RD4 immunohistochemistry: tau pathology immunoreactive for 4Rtau isoforms but not for 3R-tau isoforms. (f) RD3 immunohistochemistry.
for developing parkinsonism [1]. A previous clinico-pathological study found that the motor features of a corticobasal syndrome developed 4.1 years (2.1) after PPA onset [4]. Our patient did not develop clinical parkinsonism after 5 years from onset; however, 123I-FP-CIT-SPECT identified in vivo subclinical nigrostriatal degeneration which was related to CBD neuropathology. This clinicopathological study highlights that 123I-FP-CIT-SPECT could be a potential biomarker to identify PPA patients with underlying nigrostriatal degeneration associated with 4R FTLDtau pathology.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
(a)
(b)
(c)
(d)
(e)
(f)
e57
Acknowledgements
References
We are indebted to the Neurological Tissue Bank of the Biobanc-Hospital ClinicIDIBAPS for neuropathological studies and to brain donors for generous donations. This study was partially supported by GE Healthcare BioSciences S.A.
1. Gil-Navarro S, Lome~ na F, Cot A, et al. Decreased striatal dopamine transporter uptake in progressive non-fluent aphasia. Eur J Neurol 2013; 20: 1459–e126. 2. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006–1014. 3. Josephs KA, Duffy JR, Strand EA, et al. Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 2006; 129: 1385–1398. 4. McMonagle P, Blair M, Kertesz A. Corticobasal degeneration and progressive aphasia. Neurology 2006; 67: 1444– 1451.
Patient consent Obtained. Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
