Fabiola De Marchi

Intraspinal stem cell transplantation for amyotrophic lateral sclerosis: Ready for efficacy clinical trials?

Intraspinal stem cell (SC) transplantation represents a new therapeutic approach for amyotrophic lateral sclerosis (ALS) clinical trials. There are considerable difficulties in designing future efficacy trials, some related to the field of ALS and some that are specific to SCs or the mode of delivery. In October 2015, the most controversial points on SC transplantation were addressed during an international workshop intended to bring together international SC and ALS researchers in a public discussion on a topic for which expertise is limited. During the meeting, a discussion was started on the basic structure of the ideal clinical trial testing the efficacy and safety of SC transplantation. The current document includes a number of consensus points reflecting the design of phase II/III clinical trials.

Predicting cognitive decline in Parkinson's disease: can we ask the genes?

Parkinson’s disease dementia (PDD) is characterized by progressive cognitive decline, mainly affecting executive functions, which occurs in PD patients at least 1 year after the onset of motor symptoms, when no other causes of dementia can be detected. Such temporal cut-off allows to discriminate between PDD and Lewy body disease (LBD) in which dementia is present since the disease onset, along with parkinsonism, visual hallucinations, and fluctuations in the level of consciousness. The prevalence of dementia in patients with PD is 25%, increasing up to 80% in patients with late onset after 20 years of follow-up. In contrast, PDD has been detected in only 20% of young onset PD patients after a follow-up of more than 18 years (1). Clinical criteria for probable PDD require a diagnosis of PD (2) and a slowly progressive dementia syndrome. Typical cognitive deficits in two of four domains (attention, executive function, visuospatial function, and free recall) and at least one behavioral symptom (apathy, depression/anxious mood, hallucinations, delusions, or excessive daytime sleepiness) must be present. Exclusion criteria include unknown time interval between motor and cognitive symptoms, acute confusion, resulting from systemic diseases or drug intoxication and features compatible with vascular dementia (3). In recent years, several studies have focused on predictive markers of cognitive decline in PD. Clinical, neuroimaging, and molecular markers have been identified. Nonetheless, which markers are most reliable and applicable to clinical practice to predict the long-term prognosis of these patients still needs to be clarified.

Headache in immigrant patients: similarities and differences with Italian population

Headache is one of the most common neurological diseases. It is well known that there are differences in the perception and in the management of pain in various populations. Immigrants represent a growing portion between neurology outpatients. We analyzed the epidemiological characteristic of headache in immigrants come to our attention, in comparison with Italians. Data collected included age at immigration, age of onset of headache, headache’s type (HIS criteria), and psychiatric comorbidities. There were not substantial differences in the incidence of headache subtypes: migraine was the most frequent diagnosis in both groups, followed by tension-type headache. The incidence of depression was similar, while anxiety was significantly less frequent in immigrants. Studies on neurological diseases in immigrants are few. The data available seem to show no differences in the incidence, but rather in treatment. Our study confirms the evenness of two populations, local and foreign, afferent in a Headache Unit, according to the single similar study, except for anxiety, maybe related to language difficulties or cultural background.

Chronic obstructive pulmonary disease may complicate Alzheimer’s disease: a comorbidity problem

Background and aimChronic obstructive pulmonary disease (COPD) may be associated with worsening of cognitive performance. We studied patients with Alzheimer’s disease (AD) with and without COPD, and we analyzed, in a retrospective way, clinical and neuropsychological variables to verify if COPD plays a pejorative role on cognitive or functional autonomy in patients with dementia.MethodsWe enrolled 23 adult patients (AD-COPD) with probable AD and COPD and 23 with AD only (AD-only); they were matched for sex, age, educational level, and Mini Mental State Examination (MMSE) at the disease onset. Global cognitive status was estimated using MMSE at the first assessment and after 24 months. Memory, executive functions, praxia, and language were the other cognitive domains analyzed. The two groups were also compared for the presence of behavioral disorders (anxiety, depression).ResultsAD-COPD had worse results in executive functions screening than AD-only; no significant differences were found comparing other cognitive domains; moreover, there was no significant difference between the two groups considering the decrease in MMSE scores. AD-COPD also showed a higher presence of depression.DiscussionCOPD is known to be associated with the development of cognitive deficits, in particular, regarding for executive functions and attention, memory and logical reasoning. In this context, MMSE has a low diagnostic accuracy to underline effective cognitive impairment in AD-COPD. Our study shows a higher frequency of frontal deficits and behavioral disturbances in patients with AD and COPD than patients with AD-only. COPD could complicate the management of AD patients, thus necessitating a closer and multidisciplinary monitoring.

Ptosis and bulbar onset: an unusual phenotype of familial ALS?

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of upper and lower motor neurons that usually spare the oculomotor nerves. Here, we describe a case of two siblings with a familial bulbar-onset ALS both with ptosis manifested at the onset of the disease.

The Length of SNCA Rep1 Microsatellite May Influence Cognitive Evolution in Parkinson’s Disease

Background Alpha-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial Parkinson’s disease (PD). A previous study showed that a variant of the alpha-synuclein gene (SNCA), namely the 263 bp allele of Rep1 was associated with faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on disease progression in PD patients. Methods We recruited and genotyped for SNCA Rep1 426 PD patients with age at onset ≥40 years and disease duration ≥4 years. We then analyzed frequency and time of occurrence of wearing-off, dyskinesia, freezing of gait, visual hallucinations, and dementia using a multivariate Cox’s proportional hazards regression model. Results SNCA Rep1 263 carriers showed significantly increased risk of both dementia (HR = 3.03) and visual hallucinations (HR = 2.69) compared to 263 non-carriers. Risk of motor complications did not differ in the two groups. Conclusion SNCA Rep1 263 allele is associated with a worse cognitive outcome in PD.

Advances in stem cell therapy for amyotrophic lateral sclerosis

ABSTRACT Introduction: Amyotrophic Lateral Sclerosis (ALS) is a progressive, incurable neurodegenerative disease that targets motoneurons. Cell-based therapies have generated widespread interest as a potential therapeutic approach but no conclusive results have yet been reported either from pre-clinical or clinical studies. Areas covered: This is an integrated review of pre-clinical and clinical studies focused on the development of cell-based therapies for ALS. We analyze the biology of stem cell treatments and results obtained from pre-clinical models of ALS and examine the methods and the results obtained to date from clinical trials. We discuss scientific, clinical, and ethical issues and propose some directions for future studies. Expert opinion: While data from individual studies are encouraging, stem-cell-based therapies do not yet represent a satisfactory, reliable clinical option. The field will critically benefit from the introduction of well-designed, randomized and reproducible, powered clinical trials. Comparative studies addressing key issues such as the nature, properties, and number of donor cells, the delivery mode and the selection of proper patient populations that may benefit the most from cell-based therapies are now of the essence. Multidisciplinary networks of experts should be established to empower effective translation of research into the clinic.

A case of late-onset OCD developing PLS and FTD

Abstract We describe a 64-year-old woman, suffering from late-onset obsessive–compulsive disorder (OCD) from the age of 57, who developed dysarthria and dysphagia, spastic diplegic, and proximal muscles weakness. Needle electromyography showed no active denervation. Neuropsychological evaluation showed intact cognitive functioning. We diagnosed upper motor neuron disease (MND), with no known genetic correlates. Brain magnetic resonance (MRI) detected bilateral hippocampal atrophy with sclerosis of right hippocampus. 18F-FDG positron emission tomography (PET) showed moderate right temporal cortex thinning. Six months later, motor and behavioral symptoms worsened. Neuropsychological examination revealed long-term memory deficit and executive dysfunction. MRI and PET evidenced severe worsening of atrophy in temporal and frontal lobes. Four years later a definitive diagnosis of primary lateral sclerosis (PLS) and FTD was made. To our knowledge, this is the first report of PLS and FTD with OCD at onset.

Characterization of the c9orf72 GC-rich low complexity sequence in two cohorts of Italian and Turkish ALS cases

Abstract Large expansions of a noncoding GGGGCC repeat in the C9orf72 gene are the main cause of amyotrophic lateral sclerosis (ALS). The GGGGCC repeat is contiguous with another GC-rich region. Recent studies reported a significantly higher frequency of insertions/deletions within the GC-rich region in patients carrying the GGGGCC expansion. A GTGGT motif comprised within the GC-rich region, which joins two 100% GC sequences, was frequently deleted, supporting the hypothesis that these deletions could make the region more prone to slippage and pathological expansion. To confirm this hypothesis, we sequenced the GC-rich region adjacent the GGGGCC repeat in ALS patients, 116 C9orf72 expansion carriers, 219 non-carriers, and 223 healthy controls, from Italian and Turkish cohorts. Deletions were significantly more frequent in C9orf72 expansion carriers (6%) compared to non-carrier ALS patients (0.46%, OR =14.00, 95% CI =1.71–306.59, p = 0.003), to controls (0%, OR =16.29, 95% CI =2.12–725.99, p = 4.86 × 10−4) and to the whole cohort of non-carriers (0.2%, OR =28.51, 95% CI =3.47–618.91, p = 9.58 × 10−5). Among expansion carriers, deletions with or without the GTGGT motif were equally distributed (4 vs. 3). The frequency of insertions was not statistically different between C9orf72 expansion carriers and any other group including the whole cohort of non-carriers (p = 0.439, Fisher’s exact test). Our data confirmed the association between deletions within GC-rich region and the GGGGCC expansion in Italian and Turkish cases, although we did not confirm a role of the GTGGT element deletion. Further studies will be therefore necessary to assess the causal relationships between contiguous deletions of the GC-rich region and the GGGGCC expansion.

Marchiafava-Bignami Disease: Uncertain MRI Predictors of Outcome

Marchiafava-Bignami disease (MBD) is a rare, often fatal, toxic neurological disease mainly characterized by demyelination of the corpus callosum, with or without associated lesions of hemispheric white matter. The clinical picture is severe, and includes both neuropsychiatric features, and signs of interhemispheric disconnection. The disease can have an acute or chronic course. Neuroimaging provides the most useful information for diagnosis and prognosis. We present a 44- year-old patient suffering from subacute onset of MBD, in who diffusion-weighted MRI revealed symmetrical hyperintense lesions in the frontal region of cerebral cortex and in the body/splenium of corpus callosum. Involvement of the corpus callosum was partial; the diagnosis was rather prompt, and the treatment was appropriated. The patient, survived to the acute phase, developed a chronic dementia.