Corrigendum: PMCA-based detection of prions in the olfactory mucosa of patients with sporadic Creutzfeldt-Jakob disease.

[This corrects the article DOI: 10.3389/fnagi.2022.848991.].

Defining the phenotypic spectrum of sporadic Creutzfeldt-Jakob disease MV2K: the kuru plaque type.

The current classification of sporadic Creutzfeldt-Jakob disease identifies six major subtypes mainly defined by the combination of the genotype at polymorphic codon 129 (methionine/M or valine/V) of the prion protein gene and the type (1 or 2) of misfolded prion protein accumulating in the brain (e.g. MM1, MM2, MV1, MV2, etc.). Here, we systematically characterized the clinical and histo-molecular features associated with the third prevalent subtype, the MV2 subtype with kuru plaques (MV2K), in the most extensive series collected to date. We evaluated neurological histories, cerebrospinal biomarkers, brain MRI and EEG results in 126 patients. The histo-molecular assessment included misfolded prion protein typing, standard histologic staining and immunohistochemistry for prion protein in several brain areas. We also investigated the prevalence and topographic extent of coexisting MV2-cortical features, the number of cerebellar kuru plaques and their effect on clinical phenotype. Systematic regional typing revealed a western blot profile of misfolded prion protein comprising a doublet of 19 and 20 kDa unglycosylated fragments, with the former more prominent in neocortices and the latter in the deep grey nuclei. The 20/19 kDa fragment ratio positively correlated with the number of cerebellar kuru plaques. The mean disease duration was exceedingly longer than in the typical MM1 subtype (18.0 versus 3.4 months). Disease duration correlated positively with the severity of pathologic change and the number of cerebellar kuru plaques. At the onset and early stages, patients manifested prominent, often mixed, cerebellar symptoms and memory loss, variably associated with behavioural/psychiatric and sleep disturbances. The cerebrospinal fluid prion real-time quaking-induced conversion assay was positive in 97.3% of cases, while 14-3-3 protein and total-tau positive tests were 52.6 and 75.9%. Brain diffusion-weighted MRI showed hyperintensity of the striatum, cerebral cortex and thalamus in 81.4, 49.3 and 33.8% of cases, and a typical profile in 92.2%. Mixed histotypes (MV2K + MV2-cortical) showed an abnormal cortical signal more frequently than the pure MV2K (64.7 versus 16.7%, P = 0.007). EEG revealed periodic sharp-wave complexes in only 8.7% of participants. These results further establish MV2K as the most common 'atypical' subtype of sporadic Creutzfeldt-Jakob disease, showing a clinical course that often challenges the early diagnosis. The plaque-type aggregation of the misfolded prion protein accounts for most of the atypical clinical features. Nonetheless, our data strongly suggest that the consistent use of the real-time quaking-induced conversion assay and brain diffusion-weighted MRI allows an accurate early clinical diagnosis in most patients.

Semantic and right temporal variant of FTD: Next generation sequencing genetic analysis on a single-center cohort.

Semantic and right temporal variant of frontotemporal dementia (svFTD and rtvFTD) are rare clinical phenotypes in which, in most cases, the underlying pathology is TDP-43 proteinopathy. They are usually sporadic disorders, but recent evidences suggest a higher frequency of genetic mutations for the right temporal versus the semantic variant. However, the genetic basis of these forms is not clear. In this study we performed a genetic screening of a single-center cohort of svFTD and rtvFTD patients, aiming at identifying the associated genetic variants. A panel of 73 dementia candidate genes has been analyzed by NGS target sequencing including both causal and risk/modifier genes in 23 patients (15 svFTD and 8 rtvFTD) and 73 healthy age-matched controls. We first performed a single variant analysis considering rare variants and then a gene-based aggregation analysis to evaluate the cumulative effects of multiple rare variants in a single gene. We found 12 variants in nearly 40% of patients (9/23), described as pathogenic or classified as VUS/likely pathogenic. The overall rate was higher in svFTD than in rtvFTD. Three mutations were located in MAPT gene and single mutations in the following genes: SQSTM1, VCP, PSEN1, TBK1, OPTN, CHCHD10, PRKN, DCTN1. Our study revealed the presence of variants in genes involved in pathways relevant for the pathology, especially autophagy and inflammation. We suggest that molecular analysis should be performed in all svFTD and rtvFTD patients, to better understand the genotype-phenotype correlation and the pathogenetic mechanisms that could drive the clinical phenotypes in FTD.

Preventive pharmacological treatment in subjects at risk for fatal familial insomnia: science and public engagement.

Engaging patients as partners in biomedical research has gradually gained consensus over the last two decades. They provide a different perspective on health priorities and help to improve design and outcomes of clinical studies. This paper describes the relationship established between scientists and members of a large family at genetic risk of very rare lethal disease, fatal familial insomnia (FFI). This interaction led to a clinical trial based on the repurposing of doxycycline - an antibiotic with a known safety profile and optimal blood-brain barrier passage - which in numerous preclinical and clinical studies had given evidence of its potential therapeutic effect in neurodegenerative disorders, including prion diseases like FFI. The design of this trial posed several challenges, which were addressed jointly by the scientists and the FFI family. Potential participants excluded the possibility of being informed of their own FFI genotype; thus, the trial design had to include both carriers of the FFI mutation (10 subjects), and non-carriers (15 subjects), who were given placebo. Periodic clinical controls were performed on both groups by blinded examiners. The lack of surrogate outcome measures of treatment efficacy has required to compare the incidence of the disease in the treated group with a historical dataset during 10 years of observation. The trial is expected to end in 2023. Regardless of the clinical outcome, it will provide worthwhile knowledge on the disease. It also offers an important example of public engagement and collaboration to improve the quality of clinical science.

Superficial siderosis in long-standing pilocytic astrocytoma.

BACKGROUND: Pilocytic astrocytoma (PA) rarely spreads along neuraxis, and association with superficial siderosis (SS) and chronic signs of intracranial hypertension is exceptional. CASE REPORT: A 48-year-old woman presented with slow onset hearing loss in the past year. Clinical examination revealed dysarthria, positive Romberg test, and severe optic neuropathy. Cerebrospinal fluid (CSF) analysis showed numerous red blood cells, increased proteins and LDH, and high opening pressure. Brain and spine MRI demonstrated extensive superficial siderosis, bone remodeling of the skull base and spine, and diffuse nodular leptomeningeal enhancement. Histological examination of a nodule in the dorsal spine evidenced PA. CONCLUSION: We report a case of PA associated with dural remodeling and SS. The mechanism of SS is unclear but might be related to meningeal tumor infiltration and altered CSF composition and resorption.

PMCA-Based Detection of Prions in the Olfactory Mucosa of Patients With Sporadic Creutzfeldt-Jakob Disease.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder caused by the conformational conversion of the prion protein (PrPC) into an abnormally folded form, named prion (or PrPSc). The combination of the polymorphism at codon 129 of the PrP gene (coding either methionine or valine) with the biochemical feature of the proteinase-K resistant PrP (generating either PrPSc type 1 or 2) gives rise to different PrPSc strains, which cause variable phenotypes of sCJD. The definitive diagnosis of sCJD and its classification can be achieved only post-mortem after PrPSc identification and characterization in the brain. By exploiting the Real-Time Quaking-Induced Conversion (RT-QuIC) assay, traces of PrPSc were found in the olfactory mucosa (OM) of sCJD patients, thus demonstrating that PrPSc is not confined to the brain. Here, we have optimized another technique, named protein misfolding cyclic amplification (PMCA) for detecting PrPSc in OM samples of sCJD patients. OM samples were collected from 27 sCJD and 2 genetic CJD patients (E200K). Samples from 34 patients with other neurodegenerative disorders were included as controls. Brains were collected from 26 sCJD patients and 16 of them underwent OM collection. Brain and OM samples were subjected to PMCA using the brains of transgenic mice expressing human PrPC with methionine at codon 129 as reaction substrates. The amplified products were analyzed by Western blot after proteinase K digestion. Quantitative PMCA was performed to estimate PrPSc concentration in OM. PMCA enabled the detection of prions in OM samples with 79.3% sensitivity and 100% specificity. Except for a few cases, a predominant type 1 PrPSc was generated, regardless of the tissues analyzed. Notably, all amplified PrPSc were less resistant to PK compared to the original strain. In conclusion, although the optimized PMCA did not consent to recognize sCJD subtypes from the analysis of OM collected from living patients, it enabled us to estimate for the first time the amount of prions accumulating in this biological tissue. Further assay optimizations are needed to faithfully amplify peripheral prions whose recognition could lead to a better diagnosis and selection of patients for future clinical trials.

The novel I213S mutation in PSEN1 gene is located in a hotspot codon associated with familial early-onset Alzheimer's disease.

Mutations in presenilin 1 gene (PSEN1) are the most common causes of autosomal dominant early-onset Alzheimer's disease (EOAD). We report a novel PSEN1 mutation (I213S) that was discovered in an Italian patient with a family history of early-onset dementia, who developed a slowly progressive cognitive decline since the age of 40 years. Clinical investigations, including neuropsychological assessment, brain MRI and 18-fluorodeoxyglucose PET, as well as cerebrospinal fluid biomarkers, supported the diagnosis of EOAD. Genetic studies identified a novel missense mutation at codon 213 (I213S). Three other mutations at the same codon have been described in association with EOAD. Previous in silico, in vitro and in vivo studies indicated that these mutations affect the functional properties of γ-secretase and are most likely pathogenic. In silico algorithms suggested that even the I213S mutation has similar deleterious effects on PSEN1 structure and function. Overall, these data strongly support a role of hotspot site for the codon 213 of PSEN1, and provide evidence that the genetic variants located on this site cause EOAD.

Deep transcranial magnetic stimulation in combination with skin thermography in obesity: a window on sympathetic nervous system.

AIMS: Obesity is known to be associated with an altered thermoregulation as well as a dysregulation of sympathetic nervous system (SNS). Considering the ability of deep transcranial magnetic stimulation (dTMS) to modulate the SNS, we hypothesized a potential role of dTMS in affecting thermoregulation in obesity. Aims of the study were to monitor the effect of a single session of dTMS on body temperature in subjects with obesity, and to correlate the dTMS-induced changes in body temperature with activation of the SNS (epinephrine and norepinephrine release). METHODS: Twenty-nine subjects with obesity [5 M, 24 F; age 50 (IQR: 58, 38) yrs; BMI 36.1 (IQR: 33.9, 38.7) kg/m2] were randomized into 2 groups receiving a single session of high frequency stimulation (HF) or sham stimulation. Under neutral thermal conditions, infrared thermography was utilized to assess bilateral fingernail-beds and abdominal temperature. RESULTS: During a single session HF, the average temperature of both fingernail-beds decreased. Right-hand temperature difference was statistically greater in HF vs Sham: median = - 1.45 (IQR: - 2.0, - 1.0)  °C for HF, p = 0.009. While temperature variation in the fingernail-bed of left hand was not statistically significant in HF compared to Sham: median = - 1.26 (IQR: - 1.6, -0.5) °C, p = 0.064. Concurrently, when estimating the effect of norepinephrine variation on temperature change of fingernail-bed of left hand, a borderline significant positive association was estimated (beta = 1.09, p = 0.067) in HF. CONCLUSIONS: Deep TMS revealed to be effective in modulating temperature in subjects with obesity, partially reversing obesity-induced alterations in heat production and dissipation with a potential SNS-mediated mechanism.

Tranquillizing Effect of Passiflora incarnata Extract: Outcome on Behavioral and Physiological Indicators in Weaning Pigs with Intact Tails.

Tail docking has been used in the pig industry to decrease the occurrence of tail biting behavior. This abnormal behavior has a multifactorial origin since it is a response to simultaneous environmental, nutritional and management changes. Given the calming properties of Passiflora incarnata, we hypothesized that dietary supplementation with the extract in weaned pigs could result in a modification of behavior and physiologic indicators linked to stress. Weaned piglets (n = 120, mean body weight 9.07 ± 2.30 kg) were randomly allocated to one of two dietary treatments: control diet (CON) and CON supplemented with 1 kg/t of P. incarnata (PAS). The trial was 28 days long. The presence of skin lesions was assessed at d-1, d-10, d-19, and d-28, and saliva samples were collected for IgA and cortisol determinations at the same sampling times. Results showed the PAS group was characterized by equal growth performance as the CON group, fewer ear lesions (p < 0.05), less aggressive behavior (p < 0.001), higher enrichment exploration (p < 0.001) and lower cortisol levels (p < 0.01). Time effect was observed for tail lesions (p < 0.001) and behavioral observations (p < 0.001). Additional research is required to determine the effect of P. incarnata extract using a larger number of animals and longer period of supplementation when risks associated with tail biting are uncontrolled.

Neuroinflammation, body temperature and behavioural changes in CD1 male mice undergoing acute restraint stress: An exploratory study.

BACKGROUND: Animal models used to study pathologies requiring rehabilitation therapy, such as cardiovascular and neurologic disorders or oncologic disease, must be as refined and translationally relevant as possible. Sometimes, however, experimental procedures such as those involving restraint may generate undesired effects which may act as a source of bias. However, the extent to which potentially confounding effects derive from such routine procedures is currently unknown. Our study was therefore aimed at exploring possible undesirable effects of acute restraint stress, whereby animals were exposed to a brightly lit enclosed chamber (R&L) similar to those that are commonly used for substance injection. We hypothesised that this would induce a range of unwanted physiological alterations [such as neuroinflammatory response and changes in body weight and in brown adipose tissue (BAT)] and behavioural modification, and that these might be mitigated via the use of non-aversive handling methods: Tunnel Handling (NAH-T) and Mechanoceptive Handling (NAH-M)) as compared to standard Tail Handling (TH). METHODS: Two indicators of physiological alterations and three potentially stress sensitive behavioural parameters were assessed. Physiological alterations were recorded via body weight changes and assessing the temperature of Brown Adipose Tissue (BAT) using infra-red thermography (IRT), and at the end of the experiment we determined the concentration of cytokines CXCL12 and CCL2 in bone marrow (BM) and activated microglia in the brain. Nest complexity scoring, automated home-cage behaviour analysis (HCS) and Elevated Plus Maze testing (EPM) were used to detect any behavioural alterations. Recordings were made before and after a 15-minute period of R&L in groups of mice handled via TH, NAH-T or NAH-M. RESULTS: BAT temperature significantly decreased in all handling groups following R&L regardless of handling method. There was a difference, at the limit of significance (p = 0.06), in CXCL12 BM content among groups. CXCL12 content in BM of NAH-T animals was similar to that found in Sentinels, the less stressed group of animals. After R&L, mice undergoing NAH-T and NAH-M showed improved body-weight maintenance compared to those exposed to TH. Mice handled via NAH-M spent a significantly longer time on the open arms of the EPM. The HCS results showed that in all mice, regardless of handling method, R&L resulted in a significant reduction in walking and rearing, but not in total distance travelled. All mice also groomed more. No difference among the groups was found in Nest Score, in CCL2 BM content or in brain activated microglia. CONCLUSIONS: Stress induced by a common restraint procedure caused metabolic and behavioural changes that might increase the risk of unexpected bias. In particular, the significant decrease in BAT temperature could affect the important metabolic pathways controlled by this tissue. R&L lowered the normal frequency of walking and rearing, increased grooming and probably carried a risk of low-grade neuro-inflammation. Some of the observed alterations can be mitigated by Non-aversive handlings.

Equine-Assisted Interventions (EAIs) for Children with Autism Spectrum Disorders (ASD): Behavioural and Physiological Indices of Stress in Domestic Horses (Equus caballus) during Riding Sessions.

Equine-assisted interventions (EAIs) are well-known complementary practices combining physical activity with emotional/cognitive stimulation. They are especially suited for children with autism spectrum disorders (ASD) who need a high degree of physical and psychological enrichment. Even though EAIs have become a common practice, stress responses in horses interacting with individuals that can manifest inappropriate behaviours, such as ASD children, have not been thoroughly investigated. Our multicentre study aimed to investigate behavioural and physiological indices of stress in horses involved in EAI standardised sessions with children with ASD compared to typically developing (TD) children. A controlled within-subject design with repeated measurements involving 19 horses and 38 children was adopted. Stress-related behaviours, heart rate, heart rate variability, and eye temperature were recorded during the riding sessions. Moreover, blood samples were collected from horses before and after each session to monitor changes in blood adrenocorticotropic hormone (ACTH), cortisol, and catecholamines. Results indicate that, in general, stress responses in horses involved in EAIs did not differ as a function of the horse being ridden by children with ASD or TD. A lower sympathetic tone in horses involved in ASD sessions was found, while in the mounting and dismounting phases, horses displayed behavioural signs of stress, independently from children's behaviour. We conclude that professionals working in EAI should increase their awareness of animal welfare and refine riding practices, taking into account horse's needs.

Neuropathological Alzheimer's Disease Lesions in Nasu-Hakola Disease with TREM2 Mutation: Atypical Distribution of Neurofibrillary Changes.

Nasu-Hakola disease is a rare autosomal recessive disorder associated to mutations in TREM2 and DAP12 genes, neuropathologically characterized by leukoencephalopathy with axonal spheroids. We report the neuropathologic findings of a 51-year-old female with a homozygous mutation (Q33X) of TREM2 gene. Beside severe cerebral atrophy and hallmarks of Nasu-Hakola disease, significant Alzheimer's disease lesions were present. Neurofibrillary changes showed an atypical topographic distribution being severe at spots in the neocortex while sparing the mesial temporal structures. Our finding suggests that TREM2 genetic defects may favor Alzheimer's disease pathology with neurofibrillary changes not following the hierarchical staging of cortical involvement identified by Braak.

The Rise of the GRN C157KfsX97 Mutation in Southern Italy: Going Back to the Fall of the Western Roman Empire.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) designates a group of neurodegenerative diseases with remarkable clinical, pathological, and genetic heterogeneity. Mutations in progranulin gene (GRN) are among the most common causes of familial FTLD. The GRN C157KfsX97 mutation is the most frequent mutation occurring in Southern Italy and has been already described in a previous work. OBJECTIVE: In this study, we reported on additional cases carrying the same mutation and performed a genetic study on the whole cohort, aiming at demonstrating the existence of a founder effect and estimating the age of this mutation. METHODS/RESULTS: Based on the haplotype sharing analysis, a founder effect was highly probable, while the age of the mutation, estimated by means of DMLE+ software, resulted in a range between 52 and 82 generations, with the highest frequency at about 62 generations, 1,550 years ago. CONCLUSION: This is the first study that reports the age estimation of the most recent common ancestor for the GRN C157KfsX97 mutation recurring in Southern Italy. Mutation dating in a geographically restricted population may be useful in order to plan genetic counseling and screening programs in the field of public health.

A refinement approach in a mouse model of rehabilitation research. Analgesia strategy, reduction approach and infrared thermography in spinal cord injury.

The principles of Refinement, Replacement and Reduction (3R's) should be taken into account when animals must be used for scientific purpose. Here, a Reduction / Refinement approach was applied to the procedure of spinal cord injury (SCI), an animal model used in rehabilitation medicine research, in order to improve the quality of experiments, avoiding unnecessary suffering. The aims of this investigation were 1- to assess acute surgical pain in mice subjected to SCI, 2- to compare the efficacy of commonly used analgesia (three buprenorphine subcutaneous injection in 48 hours, 0,15 mg/kg each) with a combination of opioid and NSAID (one subcutaneous injection of 5 mg/kg carprofen before surgery followed by three buprenorphine subcutaneous injection in 48 hours, 0,15 mg/kg each) and 3- to test if Infrared Thermography (IRT) could be a potential new Refinement method to easily assess thermoregulation, an important metabolic parameter. Finally, we aimed to achieve these goals without recruiting animals on purpose, but using mice already scheduled for studies on SCI. By using behaviours analysis, we found that, despite being commonly used, buprenorphine does not completely relieve acute surgical pain, whereas the combination of buprenorphine and carprofen significantly decreases pain signs by 80%. IRT technology turned out to be a very useful Refinement tool being a non invasive methods to measure animal temperature, particularly useful when rectal probe cannot be used, as in the case of SCI. We could find that temperatures constantly and significantly increased until 7 days after surgery and then slowly decreased and, finally, we could observe that in the buprenorphine and carprofen treated group, temperatures were statistically lower than in the buprenorphine-alone treated mice. To our knowledge this is the first work providing an analgesic Refinement and a description of thermoregulatory response using the IRT technology, in mice subjected to SCI.

A unique common ancestor introduced P301L mutation in MAPT gene in frontotemporal dementia patients from Barcelona (Baix Llobregat, Spain).

The County of Baix Llobregat (Barcelona, Catalonia, Spain) presents a high prevalence of familial frontotemporal dementia (FTD) in the presence of P301L mutation in the MAPT gene. To evaluate a possible unique founder effect of P301L, and its age, the analysis of 20 single-nucleotide polymorphisms covering 50 kb and 12 single-nucleotide polymorphisms located along 30 Mb around the mutation was performed by developing 2 multiplex single-base extension reactions. In addition, families with affected and healthy individuals from France and Italy were analyzed. The FTD-affected individuals from Barcelona carried the same 50-kb haplotype linked to P301L mutation, suggesting a unique common ancestor, as opposed to French patients. Italian patients are also probably descendants of a unique ancestor, which would be different from that of Barcelona. Diversity of 30-Mb haplotypes found in Barcelona and the inference of the mutation age in these populations, among other reasons, suggest that prevalence of FTD linked to P301L MAPT mutation is the result of a locally originated mutation.

The Use of Infrared Thermography for the Monitoring of Udder Teat Stress Caused by Milking Machines.

The aim of this study was to test infrared thermography (IRT) as a possible tool for scoring teat color changes after cluster removal; thus, indirectly, to classify the short-term stress of teats caused by milking machines. Thermographic images (n = 137) from three farms were collected and evaluated to calculate the average and maximum skin surface temperatures (SSTs) at the base, center, and tip of each teat (Tavg,B, Tavg,C, Tavg,T, Tmax,B, Tmax,C, and Tmax,T). Obtained results confirmed a significant relationship between the indicators Tavg, Tmax and the levels of teat color change (level one: pink-colored teat; level two: red-colored teat; level three: blue or purple-colored teat). Nevertheless, when a teat was considered to be stressed because its scoring fell in level 3 of the color-change scale used, sensitivity and specificity in the classification of the teat status ranged respectively between 45.6% and 54.3%, and 54.4% and 59.2%, for the indicators Tavg; and 56.5% and 60.9%, and 59.7% and 61.8%, for the indicators Tmax. When a teat was considered stressed because its scoring fell between the levels 2 and 3 of the scale adopted, sensitivity and specificity were between 49.0% and 55.8%, and 58.3% and 61.8%, for the indicators Tavg; and 55.8% and 59.9%, and 60.6% and 61.4%, for the indicators Tmax. As a consequence, the low values of sensitivity and specificity do not seem to justify the development of an ad hoc infrared device for the monitoring of udder teat stress. Nonetheless, this technology can be a viable solution for a preliminary evaluation of the mechanical stress of teats if a milking system would be equipped with an infrared sensor already in place for other purposes (e.g., the monitoring of udder health status).

The Use of Infrared Thermography (IRT) as Stress Indicator in Horses Trained for Endurance: A Pilot Study.

The aim of this pilot study was to document the effects of endurance training at different intensities on heart rate (HR), blood count, serum cortisol, and maximal temperatures of different body locations, namely eye, crown, pastern pasterns, gluteus and longissimus dorsi muscle (mm), measured by infrared thermography technique (IRT) in horses trained for endurance. Possible associations among the studied parameters were also investigated. Our hypothesis was that temperature, measured by IRT after endurance training of different intensities would vary depending on the intensity and would be positively correlated with HR and serum cortisol. Eight horses were tested before and after training of different intensities (low, moderate, and high). The results partially supported our hypothesis; all the studied parameters increased after training (p < 0.05), eye temperature (ET) correlated positively with HR (p < 0.01), and crown temperature (CT) correlated positively with cortisol (p < 0.01). However, only HR and white blood cells increased with the intensity of the exercise (p = 0.0016 and p = 0.0142, respectively). Our findings suggest the evaluation of ET and CT may become a useful non-invasive tool to detect physiological stress during training and to evaluate how the horses cope with the training. Infrared thermography technique may also become a useful tool for the early identification of horses that are not fit to compete or to continue the competition. However, further studies should be conducted on a larger number of horses and during competitions to ascertain our preliminary findings.

Prion-related peripheral neuropathy in sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: To assess whether the involvement of the peripheral nervous system (PNS) belongs to the phenotypic spectrum of sporadic Creutzfeldt-Jakob disease (sCJD). METHODS: We examined medical records of 117 sCJDVV2 (ataxic type), 65 sCJDMV2K (kuru-plaque type) and 121 sCJDMM(V)1 (myoclonic type) subjects for clinical symptoms, objective signs and neurophysiological data. We reviewed two diagnostic nerve biopsies and looked for abnormal prion protein (PrPSc) by western blotting and real-time quaking-induced conversion (RT-QuIC) in postmortem PNS samples from 14 subjects. RESULTS: Seventy-five (41.2%) VV2-MV2K patients, but only 11 (9.1%) MM(V)1, had symptoms or signs suggestive of PNS involvement occurring at onset in 18 cases (17 VV2-MV2K, 9.3%; and 1 MM(V)1, 0.8%) and isolated in 6. Nerve biopsy showed a mixed predominantly axonal and demyelinating neuropathy in two sCJDMV2K. Electromyography showed signs of neuropathy in half of the examined VV2-MV2K patients. Prion RT-QuIC was positive in all CJD PNS samples, whereas western blotting detected PrPSc in the sciatic nerve in one VV2 and one MV2K. CONCLUSIONS: Peripheral neuropathy, likely related to PrPSc deposition, belongs to the phenotypic spectrum of sCJDMV2K and VV2 and may mark the clinical onset. The significantly lower prevalence of PNS involvement in typical sCJDMM(V)1 suggests that the PNS tropism of sCJD prions is strain dependent.

Stereotypic behaviours in frontotemporal dementia and progressive supranuclear palsy.

INTRODUCTION: The behavioural variant of frontotemporal dementia (bvFTD), and the Richardson variant of progressive supranuclear palsy (PSP-RS) share several clinical signs and symptoms. Since stereotypic behaviours are fairly common in bvFTD, and are also described in other degenerative dementias including Alzheimer's disease, and parkinsonisms with dementia, we aimed to examine the extent to which stereotypies also characterise PSP-RS. METHODS: We compared 53 bvFTD patients with 40 demented PSP-RS patients, seen consecutively as outpatients at four Italian Hospitals. Patients were assessed by the Neuropsychiatric Inventory (NPI); Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) for cognitive functions; Stereotypy Rating Inventory (SRI) for stereotypies; Unified Parkinson's Disease Rating Scale (UPDRS) for motor function; and Activities of Daily Living (ADL) to assess autonomy in daily life. RESULTS: The groups did not differ for age, illness duration, cognitive functions or total NPI score; PSP-RS had significantly more depressive symptoms and greater motor and autonomy compromise than bvFTD. The groups did not differ significantly on total SRI score, but bvFTD had significantly more cooking and eating stereotypies. Twenty-three (57.5%) PSP-RS and 43 (81%) bvFTD patients had at least one stereotypy; 16/23 (69.5%) PSP-RS and 9/43 (20.9%) bvFTD patients appeared aware of their stereotypies. CONCLUSION: Stereotypies were common in our demented PSP-RS patients. Further studies on earlier stage non-demented PSP patients are required to ascertain whether stereotypies are characteristic of PSP in general or are confined to PSP-RS, and whether they may be used to suggest a PSP diagnosis early in disease course.