Francesca Di Stefano

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

Bipolar affective disorder preceding frontotemporal dementia in a patient with C9ORF72 mutation: is there a genetic link between these two disorders?

The FTD includes three main clinical syndromes: the behavioural variant (bvFTD), semantic dementia and progressive non-fluent aphasia [1]. For the BvFTD, which is characterized by a rich constellation of psychiatric and behavioural symptoms, the differential diagnosis with psychiatric disorders like schizophrenia and affective disorders, may be challenging [2, 3]. Recently a hexanucleotide repeat expansion in a noncoding region of the C9ORF72 gene has been identified as the cause of chromosome 9p21-linked ALS, FTD and ALS–FTD [4, 5]. We report the case of a man who developed from the age of 42 years an affective disorder characterized by repeated manic and hypomanic episodes. The manic phases were characterized by euphoria, racing thoughts, logorrhea, very high self-esteem, artistic hyperproductivity, little need for sleep. The patient fulfilled the DSM IV criteria for bipolar affective disorder (BPAD) type I [6] and was put on a long term lithium therapy with a good clinical response; during manic phases haloperidol was administered up to the acute episode resolution. The patient worked as a teacher until the age of 57 years. A patient’s maternal uncle developed a parkinsonism at the age of 60. The patient aged 64 presented to our neurological unit because he developed euphoria, impulsivity, logorrhea, sexual disinhibition with his wife, delusional fixed ideas with repetitive behaviours. He was obsessed by the idea of cleaning or putting petrol in his car and spent all day watching sport TV shows. As many of these symptoms were present in the past BPAD episodes, the patient underwent a new psychiatric examination; low doses of haloperidol were started without any improvement, so the therapy was stopped. Later a progressive cognitive impairment appeared. Neuropsychological assessment showed marked attention and executive functions troubles, working memory impairment, anomia and verbal fluency dysfunction. Neurologic examination revealed mild parkinsonism with postural tremor, camptocormia, diffuse bradykinesia and rigidity. Extrapyramidal symptoms arose when the patient was not under antipsychotic treatment. Mutations of TARDBP and PGRN genes were excluded. The patient has been found positive for a GGGGCC hexanucleotide repeat expansion in the first intron of C9ORF72 gene ([70 repeats). Brain MRI showed bilateral frontotemporal atrophy, prominent in frontal areas (Fig. 1). The orbitofrontal cortex was more involved than the dorsolateral prefrontal cortex; moreover there was a significant involvement of the fronto-insula and anterior cingulate gyrus. Perfusion SPECT demonstrated reduction of uptake in the left frontotemporal and right frontoparietal regions (Fig. 1). Structural and functional neuroimaging findings G. Floris G. Borghero A. Cannas F. D. Stefano F. Marrosu Department of Neurology, Azienda Universitaria-Ospedaliera of Cagliari and University of Cagliari, Cagliari, Italy

The phenotypical core of Alzheimer's disease-related and nonrelated variants of the corticobasal syndrome: A systematic clinical, neuropsychological, imaging, and biomarker study

The corticobasal syndrome (CBS) constitutes a neurodegenerative disease spectrum with substantial phenotypical or biological heterogeneity, requiring large or multimodal studies to identify its clinico‐biological signature while disentangling Alzheimers disease (AD)‐related from non‐AD‐related CBS.

EEG functional network topology is associated with disability in patients with amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS) is one of the most severe neurodegenerative diseases, which is known to affect upper and lower motor neurons. In contrast to the classical tenet that ALS represents the outcome of extensive and progressive impairment of a fixed set of motor connections, recent neuroimaging findings suggest that the disease spreads along vast non-motor connections. Here, we hypothesised that functional network topology is perturbed in ALS, and that this reorganization is associated with disability. We tested this hypothesis in 21 patients affected by ALS at several stages of impairment using resting-state electroencephalography (EEG) and compared the results to 16 age-matched healthy controls. We estimated functional connectivity using the Phase Lag Index (PLI), and characterized the network topology using the minimum spanning tree (MST). We found a significant difference between groups in terms of MST dissimilarity and MST leaf fraction in the beta band. Moreover, some MST parameters (leaf, hierarchy and kappa) significantly correlated with disability. These findings suggest that the topology of resting-state functional networks in ALS is affected by the disease in relation to disability. EEG network analysis may be of help in monitoring and evaluating the clinical status of ALS patients.

Constructional apraxia in frontotemporal dementia associated with the C9orf72 mutation: Broadening the clinical and neuropsychological phenotype

Abstract In our study we analysed clinical and neuropsychological data in a cohort of 57 Sardinian patients with FTD (55 apparently unrelated and two belonging to the same family), who underwent genetic screening for the C9orf72 mutation. Eight out of 56 patients were found positive for the C9orf72 mutation representing 14% of the entire cohort and 31.6% of the familial cases (6/19). C9orf72 mutated patients differed from the other FTD cases of the cohort for a younger age of onset, higher frequency of familial history for FTD and higher prevalence of delusional psychotic symptoms and hallucinations. In the neuropsychological assessment, C9orf72 mutated patients differed from non-mutated for the high frequency of visuospatial dysfunction regarding constructional apraxia (p = 0.02). In conclusion, our study confirms that Sardinian FTD patients have peculiar genetic characteristics and that C9orf72 mutated patients have a distinctive clinical and neuropsychological profile that could help differentiate them from other FTD patients. In our cohort we found that constructional apraxia, rarely reported in FTD, can properly discriminate between C9orf72 mutated and non-mutated patients and contribute to broaden the neuropsychological profile in frontotemporal dementia associated with this mutation.

C9ORF72 repeat expansion and bipolar disorder - is there a link? No mutation detected in a Sardinian cohort of patients with bipolar disorder

Recently (1), we described a patient with C9ORF72 repeat expansion (defined as more than 30 repeats) and a long history of bipolar disorder (BD) type I fulfilling the DSM-IV criteria (2), who developed behavioral frontotemporal dementia (bvFTD) at the age of 64 years. Age at onset of BD was 42 years. The patient responded well to long-term lithium therapy and low doses of haloperidol during the manic phases. Subsequently, we found another patient diagnosed with FTD who had received a diagnosis of BD at the age of 20 years and developed the first FTD symptoms when he was 51 years old. In both cases, there was no family history of BD; the first patient had a family history of Parkinson’s disease, and the second patient had a history of FTD. Meisler et al. (3) screened 89 patients with familial BD and found one two-generation family with BD with an expanded C9ORF72 repeat; in this family, the parent developed BD in the seventh decade and subsequently progressed to FTD, whereas the son was diagnosed with BD in the third decade of life. The authors concluded that C9ORF72 was not a major contributor to BD. Galimberti et al. (4) studied two cohorts of patients composed, respectively, of 206 German and 100 Italian patients with BD and found only one German patient carrying a C9ORF72 repeat expansion. The patient with the mutation was diagnosed with BD at the age of 37 years, had familiarity for Alzheimer’s disease, a negative family history for psychiatric disorders, and no signs of dementia at her last clinical interview at the age of 46 years. To further investigate the link between this repeat expansion and BD, we screened 206 Sardinian patients with BD for C9ORF72 repeat expansion with a technique that has been previously described (5). Sardinians have distinctive genetic characteristics compared with other Europeans and mainland Italians (6). The sample was comprised of 206 patients [65 male and 141 female; age at onset (mean standard deviation) = 26.75 10.75 years] diagnosed using DSM-IV criteria (2) and the Schedule for Affective Disorder and Schizophrenia–Lifetime Version (SADS-L) (7) who were recruited at the Lithium Clinic of the Clinical Psychopharmacology Centre of the University of Cagliari (Cagliari, Italy). Eighty patients had a family history of BD and the other 126 patients had sporadic BD. We did not find any patient with the mutation in our cohort. Taken together, these studies, conducted in different populations, suggest that C9ORF72 mutation is very rare in familial and sporadic BD (0–1%) while its frequency is significantly higher in patients with FTD or amyotrophic lateral sclerosis (8, 9). Considering the low number of patients identified by the different studies, it can be hypothesized that C9ORF72 mutations have a causative role only in rare cases of BD. It is possible that C9ORF72 mutations play a role both in neurodevelopment and in neurodegeneration, predisposing to BD in some cases and causing FTD in others (3). Meisler et al. (3) observed that C9ORF72 expansion may be associated with a form of BD that presents clinically with a classic phenomenology and progression to neurodegenerative disease. To our knowledge, only five patients with BD carrying a C9ORF72 mutation have been described in the literature (1, 3, 4). Three of these patients developed FTD after a long history of BD, while in the other two patients, the onset of FTD in later life cannot be ruled out, considering the young age of these subjects and the short period of follow-up. Therefore, an alternative hypothesis is that long-lasting BD preceding FTD represents a long prodromal phase of FTD that mimics the psychiatric disorder before the onset of

Capgras syndrome in Parkinson’s disease: two new cases and literature review

The Capgras syndrome (CS) is a rare psychiatric disorder. CS is classified as a delusional misidentification syndrome. Initially, CS was described in paranoid schizophrenia and schizoaffective disorders. CS has also been reported in neurodegenerative diseases such as Alzheimer’s disease and Lewy body dementia. To date, there are very few descriptions of the occurrence of CS in idiopathic Parkinson’s disease (PD), with or without dementia. Considering the recent observation of two new cases in PD patients, a systematic overview of the literature published between 1976 and 2016 reporting CS in PD was conducted. The purpose of this article is to examine the phenomenon in people with PD with and without dementia, the psychopathologic context in which it happened, the role played by the dopaminergic medications and to define useful therapeutic strategies. Our CS cases occurred in two elderly patients with advanced PD and cognitive impairment, respectively, after an acute stressor event and after an increase of the total daily dose of levodopa. In light of our observations and the cases reported in the literature, we argue that CS is an acute or subacute psychotic disorder occurring mostly in PD with dementia. Besides, the increase in brain dopamine levels induced by acute stressful events and/or dopamine-enhancing medications should be considered as a possible causal mechanism of CS in patients with advanced stages of PD and cognitive decline.

Phenotypic variability related to C9orf72 mutation in a large Sardinian kindred

Abstract We investigated intrafamilial phenotypic variability in carriers of the C9orf72 mutation, analysing clinical, neuropsychological and imaging characteristics of various members from a large Sardinian kindred with FTD or ALS. We compared these with those of C9 + patients in our ALS and FTD cohorts. Results showed that three patients carried the C9orf72 mutation: two with ALS and one with FTD and Parkinsonism. C9 + patients in our bvFTD Sardinian cohort had a higher frequency of Parkinsonism than non-mutated patients (75% vs. 36.3%, p <0.02). Parkinsonism was present in 2.7% of our ALS cohort and 3.3% of the C9 + patients. The prevalence of Parkinsonism in C9 + patients in the bvFTD and ALS cohorts showed a statistically significant difference (p <0.006). In conclusion, Parkinsonism was frequently associated with FTD but not ALS in a large Sardinian family, a finding reflected in the wider C9orf72 associated Sardinian ALS and FTD populations.

Multiple Spontaneous Cerebral Microbleeds and Leukoencephalopathy in PSEN1-Associated Familial Alzheimer's Disease: Mirror of Cerebral Amyloid Angiopathy?

Cerebral microbleeds (CMB) might reflect specific underlying vascular pathologies like cerebral amyloid angiopathy (CAA). In the present study we report the gradient-echo MRI pattern of two siblings with P284S PSEN1 mutation. T2* gradient-echo images of the two subjects demonstrated multiple microbleeds in lobar regions. The role and causes of CMB in sporadic Alzheimers disease (AD) patients have not been clearly established and useful contributions could derive from familial AD studies. Furthermore, since CAA is a potential risk factor for developing adverse events in AD immunization trials, the identification in vivo of CAA through non-invasive MRI methods could be useful to monitoring side effects.

Isolated bipallidal lesions caused by extrapontine myelinolysis.

An 89-year-old woman developed bradykinesia, mutism, and apathy after a rapid correction of hyponatremia caused by repeated vomiting. Brain MRI showed bipallidal involvement that improved at follow-up (figure 1, figure 2). The patient’s clinical history and neuroimaging are suggestive of extrapontine myelinolysis. This disease involves basal ganglia but the globus pallidus is usually spared or not singly involved.1 A patient with bipallidal extrapontine myelinolysis has been previously described.2 Toxic, hypoxic, and metabolic causes of bipallidal involvement were excluded in our patient. Extrapontine myelinolysis should be included in the differential diagnosis of patients with a history of hyponatremia, subacute parkinsonism, and bipallidal lesions on MRI.