Emanuela Costantino

Frontotemporal dementia with psychosis, parkinsonism, visuo-spatial dysfunction, upper motor neuron involvement associated to expansion of C9ORF72: a peculiar phenotype?

Dear Sirs, From 2006, a locus on chromosome 9p21 has been associated with a large proportion of ALS and FTD [1–3]. Recently, two independent groups have identified a hexanucleotide repeat expansion in noncoding region of the C9ORF72 gene as the cause of chromosome 9p21-linked ALS-FTD [4, 5]. We report the case of a 64-year-old man who presented with a 3-year history of delusional mystic thoughts, auditive, visual, and olfactory hallucinations, and hyperreligiosity. The patient later developed progressive apathy, dysphoric mood, hyperphagia, self-care reduction, and progressive cognitive decline with motor retardation. The mans father had died at age 68 after committing suicide, and his older brother developed parkinsonism associated with behavioral disturbances at age 60 and died 2 years later. Neuropsychological assessment of this patient, performed 3 years after the onset of neurological symptoms, demonstrated bradyphrenia, marked impairment of attention and executive functions, marked constructional apraxia, mild visual and verbal long-term memory deficit, mild anomia, emotional lability, fatuity, and mild utilization behavior. Blood exams, thyroid antibodies and hormones, vitamin B12, folic acid, and TPHA were all normal. Neurological examination revealed symmetric akinetic-rigid syndrome characterized by hypomimia, dysarthria, camptocormia with anterocollis, and diffuse bradykinesia. Brain MRI documented atrophy mainly frontotemporal but with consistent posterior region involvement (Fig. 1). Perfusion SPECT with 99Tc-ethylene cystine dimer (ECD) showed a marked reduction of the uptake in the frontotemporal and parietal regions bilaterally (Fig. 1). A few months after the first neurological assessment, the patient had a rapid progression to a severe dementia and developed marked pyramidal involvement of upper and lower limbs with an inability to walk. The patient became anarthric, dysphagic, and developed constipation. The nature of the dysarthria was both pseudobulbar and extrapyramidal. Lower motor neuron signs or symptoms were not present. Later the patient was admitted to a surgical department for intestinal sub-occlusion; during the hospitalization, a pulmonary embolism (PE) occurred. The patient died 4 years after the first neurological manifestations. Mutations of TARDBP, MAPT, and PGRN genes were excluded. The patient has been found positive for a GGGGCC hexanucleotide repeat expansion in the first intron of C9ORF72 gene (>50). Our patient developed a dementia with prominent behavioral disturbances at presentation, characterized mostly by psychosis with mystic themes. The neuropsychological evaluation demonstrated a marked cognitive impairment with predominant frontal syndrome. An important involvement of visuo-spatial functions was also found (Fig. 2). This cognitive impairment, associated with multimodal hallucinations and parkinsonism, which presented before the onset of upper motor neuron signs, raised a differential diagnosis between FTD and dementia with Lewy bodies (DLB). A few cases have been reported with similar diagnostic difficulties [6]. The parkinsonism was not drug-induced. The dementia profile of our patient was consistent with a behavioral variant of FTD. He presented a positive family history for similar disturbances. Some features of our case are atypical for FTD, like psychosis, constructional apraxia associated with the frontal syndrome, atrophy, and perfusional deficit extended to posterior cortical areas. Hallucinations are possible but not common in FTD [7], whereas they are a core clinical feature in the diagnostic criteria of DLB [8]. Of note, some clinical aspects of our case have been reported in patients with ALS-FTD linked to the locus 9p21, such as the presence of parkinsonism, psychosis, visuo-spatial impairment, and brain atrophy with parietal and occipital lobe involvement [9, 10]. We propose that delusions with multimodal hallucinations at presentation, visuo-spatial dysfunction, and frontotemporal brain atrophy also involving posterior areas could be aspects of a possible distinctive phenotype of FTD-parkinsonism-upper motor neuron disease linked to the C9ORF72 gene hexanucleotide expansions. Fig. 1 a–c Brain MRI T1-weighted transversal scans showing bilateral frontotemporal and posterior cerebral areas atrophy. d–f Perfusion single-photon emission computed tomography (SPECT) with 99Tc-ethylene cystine dimer (ECD). The transversal ... Fig. 2 Severe constructional apraxia demonstrated by the copy of a simple drawing

Behavioral, neuropsychiatric and cognitive disorders in Parkinson's disease patients with and without motor complications.

BACKGROUND Parkinsons disease (PD), commonly defined as a hypokinetic movement disorder, is hampered by the appearance of motor complications (MC), including dyskinesias and motor fluctuations, and non-motor symptoms such as behavioral, neuropsychiatric and cognitive disorders, which, in the last years, are gaining increasing attention. The factors affecting MC and these non-motor symptoms are still largely unknown and their interactions are not yet fully evaluated. OBJECTIVE To identify the presence of behavioral, neuropsychiatric and cognitive disorders in PD patients with and without MC and to evaluate their association with MC. METHODS Consecutive PD patients received a comprehensive structured clinical evaluation including pharmacologic treatment, MC and non-motor symptoms such as reward-seeking behaviors, neuropsychiatric symptoms (depression, anxiety, psychoses and hallucinations) and dementia. RESULTS 349 patients were included in this analysis. Patient with MC showed enhanced frequency of dementia (p < 0.001), anxiety, depression and psychoses (p < 0.01). A higher frequency of impulse control disorders was detected in patients with dyskinesias (22.2% - p < 0.001) and motor complications (12.2% - p < 0.05). Dyskinesias were significantly more present in patients with hypersexuality (p < 0.05) and compulsive shopping (p < 0.001), while they were not significantly associated with pathological gambling and binge eating. Patients with dyskinesias also had significantly higher frequency of dopamine dysregulation syndrome, hallucinations and delusions (p < 0.001), with the exception of delusional jealousy. DISCUSSION We found a higher frequency of behavioral, neuropsychiatric and cognitive disorders in patients with MC. The lack of detection of dyskinesias in several PD patients with pathological gambling in our study represents a very interesting issue. While binge eating mainly seems to be related to the use of dopamine agonists, the significant lack of association between dyskinesias and delusional jealousy suggests the hypothesis of a possible underlying psychopathological predisposition rather than a mere pharmacologic effect in PD patients with these behavioral complications.

A patient carrying a homozygous p.A382T TARDBP missense mutation shows a syndrome including ALS, extrapyramidal symptoms, and FTD

We have recently published data showing that a founder mutation of the TARDBP gene (p.A382T) accounts for approximately one third of amyotrophic lateral sclerosis (ALS) cases on the Mediterranean island of Sardinia (Chiò et al., 2011). In that report, we identified a 53-year-old man carrying a homozygous A382T missense mutation of the TARDBP gene with a complex neurological syndrome including amyotrophic lateral sclerosis, parkinsonian features, motor and vocal tics, and frontotemporal dementia (FTD). Due to the uniqueness of this case, here we provide a detailed clinical description, as well as neurophysiological, neuropsychological, and neuroimaging data for that case and his extended family.

Pisa syndrome in a patient with progressive supranuclear palsy

Dear Professor Kaye, Pisa syndrome (PS) is an abnormal posture characterized by a tonic flexion of the trunk to one side accompanied by a slight rotation in the sagittal plane, originally described as the consequence of acute axial dystonia related to neuroleptic administration. Subsequently PS has been reported in patients treated with antiemetics, antidepressants, cholinesterase inhibitors and dopamine agonists. A similar picture may also occur as an idiopathic phenomenon and in neurodegenerative diseases, including parkinsonism. With regard to parkinsonism, although PS has been previously indicated as a red flag for multiple system atrophy (MSA), this abnormal posture is not infrequently observed in patients with typical Parkinson’s disease (PD) and other atypical parkinsonism disorders such as dementia with Lewy bodies (DLB). However, PS has not yet been described in patients with progressive supranuclear palsy (PSP). We describe a patient affected by PSP who developed a dystonic lateral flexion of the trunk compatible with the diagnosis of PS. The patient was a 69-year-old man who manifested postural instability with unexplained falls at 66 years of age. No history of substance abuse, head trauma, or family history of neurodegenerative disorder was noted. His past medical history was remarkable for hyperthyroidism treated with methimazole. During this time, the relatives referred to alterations of mood and behavior with apathy, loss of interest in ordinary pleasurable activities and associated anxiety. The patient was initially treated with antidepressant drugs such as mirtazapine (30 mg/day) and escitalopram (10 mg/day) with mild improvement of mood disorders. During the following two years, impairment of postural stability with frequent falls and visual disturbances were noted. He also complained of sleep disorders mainly characterized by insomnia, and mirtazapine and escitalopram were suspended. When admitted to our Movement Disorders Centre, neurological examination showed prominent postural instability with falls, symmetric akinesia and rigidity, proximal more than distal, and vertical supranuclear palsy. Mild dysphagia and dysarthia with occasional echolalia and palilalia were registered. Neuropsychological examination showed a mild/moderate cognitive deficit with a score of 23/30 on the Mini Mental State Examination, apathy, impairment in abstract thought and decreased verbal fluency. Treatment with levodopa/carbidopa up to 100/25 mg four times per day caused poor response of parkinsonism and was subsequently suspended because of severe nausea and vomiting. A brain MRI scan was normal, while a Iodine-N-omega-fluoropropyl-2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane (I-FP-CIT) single photon emission CT (SPECT) scan (DatSCANTM Nycomed Amersham plc, Little Chalfont, Buckinghamshire, UK) demonstrated bilateral abnormal dopamine transporter (DAT) binding in the striatum,