Nonfluent Variant of Primary Progressive Aphasia With Right Hemisphere Atrophy – A Phenotype of Corticobasal Degeneration?

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Authors:  Jos S. Becktepe, Jan Sedlacik, Holger Jahn and Kai Boelmans

Article first published online:   30 JUN 2015 | DOI: 10.1002/mdc3.12209

New criteria for the diagnosis of corticobasal degeneration (CBD) include a spectrum of tauopathy disorders that encompasses conditions such as corticobasal syndrome, frontal behavioral-spatial syndrome, progressive supranuclear palsy (PSP), and the nonfluent variant of primary progressive aphasia (naPPA).[1, 2] These revised criteria give higher cortical deficits, including language impairments, an augmented role in the symptomatology of CBD. Aphasia, for example, has been found to occur during the full course of CBD in 52% of pathologically proven cases.[1] But whereas a predominant atrophy of the language-dominant left hemisphere is required for diagnosis of naPPA,[3, 4] the clinical phenotype of CBD associated with aphasia does not seem to be correlated with the side of atrophy. Here, we describe the initial presentation of naPPA in a patient with right hemisphere atrophy, but left hemisphere language dominance, who developed a clinical phenotype of CBD.

A 61-year-old, right-handed Caucasian male presented to the memory clinic at the University Medical Center Hamburg-Eppendorf (Hamburg, Germany) in November 2012 with a 12-month history of progressive speech impairment. His spontaneous articulation was decelerated, halting, and slightly disprosodic, and he preferentially used short, truncated sentences with a subtle agrammatism. The cookie theft test revealed a discrete slowing in recall of words in spontaneous discourse and occasional thought blockings. However, single-word comprehension, general object knowledge, and overall naming were relatively preserved. Neurological examination revealed slightly retracted eyelids with characteristic expression of “perpetual surprise”. Visually triggered pro- and antisaccades showed a reduced saccade velocity, but normal latency and amplitude. Cortical release signs, such as the glabellar and palmomental reflexes, were positive, and a bimanual test revealed an impairment of reciprocal coordination. Beyond that, no extrapyramidal symptoms, apraxia, or myoclonus could be objectively demonstrated.

General cognitive assessment in 2012 revealed normal results in Mini–Mental Status Examination (30 points) and Clock Drawing Test (1 point). A comprehensive neuropsychological examination using the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) test battery detected verbal executive deficits in phonemic (z < −1.5) and semantic (−1.5 < z < −1) fluency. Attentional performance and mental flexibility were clearly below average (z < −1.5). In contrast, verbal memory and visuospatial memory (Wechsler Memory Scale) were unimpaired with no intrusion errors. Performance on the Boston Naming Test was then still normal.

In 2012, cerebrospinal fluid (CSF) routine parameters and polymerase chain reaction screening for neurotropic viruses revealed no pathological results. CSF proteins for Alzheimer's disease were unremarkable (total tau: 352 pg/mL; reference, <370 pg/mL; phosphorylated tau: 57 pg/mL; reference, <66 pg/mL; Aβ42 level: 1,275 pg/mL; reference, >562 pg/mL). However, 1 year later a marginally increased total tau protein (389 pg/mL; reference, <370 pg/mL) was detected.

On a follow-up visit in November 2013, the patient's agrammatism had slightly worsened. In addition, a neurological examination now revealed a hypokinetic-rigid syndrome on the left side of his body, hypomimia with reduced blink frequency, and hypophonia as well as a mild flexed dystonic posture of the left arm. His handwriting and spiral drawing were normal. The applause sign was now clearly positive. The patient was treated with levodopa/benserazide 250/25 mg three times a day and physical therapy with a moderate benefit. UPDRS-III score improved by 31% (from 16 to 11 points).

Although the patient and his wife denied any family history of movement or psychiatric disorders, a comprehensive genetic analysis was performed. This analysis demonstrated no pathogenetic gene mutations in the genes coding for microtubule-associated protein tau, granulin, chromosome 9 open reading frame 72, valosin-containing protein, charged multivesicular body protein 2B, and TAR DNA-binding protein 43.

Imaging measurements were performed in February 2014: Figure 1 summarizes results of T1-weighted MRI (Siemens Skyra, 3T; Siemens Healthcare, Erlangen, Germany) and 18F-fluorodeoxyglucose PET (18FDG-PET). Single-subject voxel-based statistical morphometry, as proposed by Mühlau et al., revealed a significant gray matter reduction in the right frontal and temporal lobes, encompassing the hippocampal region.[5] In addition, 18FDG-PET demonstrated an extensive right-sided fronto-temporo-parietal hypometabolism. Functional MRI (fMRI) unequivocally localized Broca's area in the inferior frontal gyrus of the left hemisphere, excluding the possibility of a right hemisphere language dominance.[6]


Figure 1. (A) T1-weighted MRI (T1-w MRI) and (B) superposition of single-subject voxel-based statistical morphometry (VBM) on a three-dimensional surface render of the patient's individual brain demonstrates a significant gray matter reduction in the right frontal and temporal lobe (brown color; two-sample, one-tailed t test; t = 2.74; P < 0.005). Gray matter volume was total intracranial volume and age corrected. (C) 18FDG-PET shows an extensive hypometabolism in large parts of the right hemisphere and, notably, a small part of the left frontal lobe (blue color; two-sample, one-tailed t test; t = 2.69;P < 0.005). (D) Broca's area is localized in the inferior frontal gyrus of the left hemisphere using an fMRI for word generation (t-value threshold for activation significance is t ≥ 4.84).

Our findings demonstrate that the CBD phenotype presenting with naPPA can be associated with right hemisphere atrophy despite an intact left hemisphere dominant language network. This constellation does not match the imaging supported PPA classification criteria for the nonfluent variant, which call for a pattern of left hemisphere atrophy.[3] In CBD, however, no clear association between language performance and side of atrophy has been found.[7, 8] Thus, the language impairments in CBD do not appear to depend solely on the atrophy of networks in the language-dominant hemisphere. Concordant with this finding, CBD symptoms, such as apraxia or visuospatial dysfunction, are virtually always bilateral, even when the atrophy is asymmetric.[9] Furthermore, we also noted primitive reflexes, such as those exhibited by this patient, combined with altered bimanual coordination, might signal a frontoexecutive dysfunction that goes beyond an isolated naPPA diagnosis.


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