Cultural adaptation and clinical validation of Rapid Cognitive Screening Test in Turkish.

BACKGROUND: The Rapid Cognitive Screen (RCS) is a brief, easy to administer score screening tool for cognitive dysfunction which can be very useful for cognitive screening in busy clinical settings. We aimed to cross-culturally adapt and validate RCS in Turkish. METHODS: A total of 172 community-dwelling older participants from geriatric and neurology clinics, aged 60 and older were included. The translation and cultural adaptation process was carried out in five stages: (i) two initial translations from English to Turkish; (ii) combination of these two translations; (iii) backward translations; (iv) an expert committee that consisted of three geriatricians and two neurologists, one Turkish lecturer reviewed to compare backward translations with the English test; and (v) pretest. The inter-rater reliability and test-retest reliability were performed. To diagnose each type of dementia, gold standard diagnostic criteria specifically defined for each dementia were used. Performances of RCS test for dementia and mild cognitive impairment (MCI) were analyzed by using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). The receiver operating characteristic analysis was performed to determine the area under the curve (AUC) with 95% confidence intervals (CI). RESULTS: Among participants, 37.2% were considered as cognitively normal, 25.6% with MCI and 37.2% with dementia. The sensitivity, specificity, PPV, and NPV of RCS (cut-off point of 4) for dementia were 89.06%, 92.56%, 87.7%, and 93.5%, respectively whereas the values were 77.27%, 51.56%, 52.3%, and 76.7% for MCI with a cut-off point of 8. The RCS predicted dementia (AUC = 0.972, 95% CI: 0.935-0.991) and MCI (AUC = 0.720%, 95% CI: 0.626-0.802). CONCLUSION: The cross-cultural adaptation was successfully achieved. The Turkish-RCS was found to be a reliable and valid test for screening of cognitive dysfunction.

Novel frameshift CTSF mutation causing kufs disease type B mimicking frontotemporal dementia-parkinsonism.

Adult-onset neuronal ceroid lipofuscinoses (ANCLs, Kufs disease-KD) are rare, inherited, progressive, neurodegenerative, lysosomal storage diseases. Mutations in cathepsin F (CTSF) were linked to KD type B. Conversely, Frontotemporal dementia (FTD) is the second most common type of presenile dementia and Parkinsonism is a mostly common accompanying feature. Due to pronounced behavioral, cognitive, and motor features in the patients with KD type B, mutations in CTSF may resemble FTD-parkinsonism. Here, we present a case of KD type B with a novel homozygous frameshift pathogenic variant (p.Gly439Alafs*36) in the Cathepsin F (CTSF) gene presenting behavioral changes, cognitive disturbances and parkinsonism with a family history mimicking FTD-parkinsonism.

Identification of metabolic correlates of mild cognitive impairment in Parkinson's disease using magnetic resonance spectroscopic imaging and machine learning.

OBJECTIVE: To investigate metabolic changes of mild cognitive impairment in Parkinson's disease (PD-MCI) using proton magnetic resonance spectroscopic imaging (1H-MRSI). METHODS: Sixteen healthy controls (HC), 26 cognitively normal Parkinson's disease (PD-CN) patients, and 34 PD-MCI patients were scanned in this prospective study. Neuropsychological tests were performed, and three-dimensional 1H-MRSI was obtained at 3 T. Metabolic parameters and neuropsychological test scores were compared between PD-MCI, PD-CN, and HC. The correlations between neuropsychological test scores and metabolic intensities were also assessed. Supervised machine learning algorithms were applied to classify HC, PD-CN, and PD-MCI groups based on metabolite levels. RESULTS: PD-MCI had a lower corrected total N-acetylaspartate over total creatine ratio (tNAA/tCr) in the right precentral gyrus, corresponding to the sensorimotor network (p = 0.01), and a lower tNAA over myoinositol ratio (tNAA/mI) at a part of the default mode network, corresponding to the retrosplenial cortex (p = 0.04) than PD-CN. The HC and PD-MCI patients were classified with an accuracy of 86.4% (sensitivity = 72.7% and specificity = 81.8%) using bagged trees. CONCLUSION: 1H-MRSI revealed metabolic changes in the default mode, ventral attention/salience, and sensorimotor networks of PD-MCI patients, which could be summarized mainly as 'posterior cortical metabolic changes' related with cognitive dysfunction.

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice.

BACKGROUND: The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations. OBJECTIVE: To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. METHODS: Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype. RESULTS: Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. CONCLUSION: With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. © 2021 International Parkinson and Movement Disorder Society.

TREM2 variants as a possible cause of frontotemporal dementia with distinct neuroimaging features.

BACKGROUND AND PURPOSE: Nasu-Hakola disease (NHD) is a rare, autosomal recessive disorder characterized by skeletal and neurological symptoms. Behavioral symptoms with cognitive impairment may mimic the behavioral variant of frontotemporal dementia (bvFTD) and other early-onset dementias. Our patients were analyzed and the literature was reviewed to delineate neurological and neuroimaging findings suggestive of NHD. METHOD: Fourteen patients carrying a pathogenic mutation in the TREM2 gene were found in our database. Demographic, clinical, laboratory and radiological data were retrieved and analyzed. RESULTS: The presenting clinical picture was behavioral changes with cognitive decline resembling bvFTD in all patients. The mean age was 37.1 ± 4.97 years and the mean duration of the disease was 8.9 ± 3.51 years. Only two patients had typical bone cysts. Seven patients had bilateral calcification of the basal ganglia in computed tomography of the brain. Magnetic resonance imaging of the brain revealed severe atrophy of the corpus callosum, enlargement of the ventricles, atrophy of the caudate nuclei and periventricular white matter changes in all patients. Symmetrical global atrophy of the brain mainly affecting frontoparietal and lateral temporal regions were observed in all cases, and 13 patients had atrophy of the hippocampus. Cerebrospinal fluid examination of 10 patients showed elevated protein levels in six and the presence of oligoclonal bands in four patients. CONCLUSION: A combination of white matter changes, enlarged ventricles, atrophy of the caudate nuclei and thinning of the corpus callosum in magnetic resonance imaging strongly suggests NHD in patients with FTD syndrome. Molecular genetic analysis should be performed in suspected cases, and families should receive genetic counseling.

Neurological features and outcomes of Wilson's disease: a single-center experience.

Wilson's disease (WD) is an autosomal recessive genetic disorder of copper metabolism, and WD patients can present with neurologic symptoms. We aimed to report the general characteristics and prognosis of a Turkish series of WD patients with neurological manifestations. A total of 12,352 patients were screened from the patient database, and 53 WD patients were included. Patients were classified based on the predominant neurological syndrome type including tremor, dystonia, parkinsonism, or discrete neurological signs and were classified as having "good outcome," "stable," and "poor outcome" according to their treatment response. There were 32 male and 21 female patients, aged 20-66 years. The mean follow-up was 11.3 ± 4.56 years. Sixty-two percent of patients presented predominantly with neurological symptoms. Neurological WD diagnosis was established after a mean time delay of 2.3 years from the WD diagnosis. The most common neurological manifestation was dystonia, followed by tremor and parkinsonism. Fifteen patients had a family history of WD. Consanguinity was present in 20 patients. Patients were treated with D-penicillamine, trientine, zinc salts, or their combinations. Besides the main treatments, 41 patients were on symptomatic treatment for neurologic symptoms. Thirty-six patients had a "good outcome," five patients were stable, and six patients had "poor outcome." Post-chelation neurological worsening was observed in 11 patients. WD should be considered in differential diagnosis in any patient with unexplained neurologic symptoms. Early diagnosis is important, and appropriate treatment should be promptly initiated to prevent progressive and irreversible damage, with good prognosis and stable disease in the majority of the patients with treatment compliance.

The cerebral blood flow deficits in Parkinson's disease with mild cognitive impairment using arterial spin labeling MRI.

Parkinson's disease (PD) with mild cognitive impairment (PD-MCI) is currently diagnosed based on an arbitrarily predefined standard deviation of neuropsychological test scores, and more objective biomarkers for PD-MCI diagnosis are needed. The purpose of this study was to define possible brain perfusion-based biomarkers of not only mild cognitive impairment, but also risky gene carriers in PD using arterial spin labeling magnetic resonance imaging (ASL-MRI). Fifteen healthy controls (HC), 26 cognitively normal PD (PD-CN), and 27 PD-MCI subjects participated in this study. ASL-MRI data were acquired by signal targeting with alternating radio-frequency labeling with Look-Locker sequence at 3 T. Single nucleotide polymorphism genotyping for rs9468 [microtubule-associated protein tau (MAPT) H1/H1 versus H1/H2 haplotype] was performed using a Stratagene Mx3005p real-time polymerase chain-reaction system (Agilent Technologies, USA). There were 15 subjects with MAPT H1/H1 and 11 subjects with MAPT H1/H2 within PD-MCI, and 33 subjects with MAPT H1/H1 and 19 subjects with MAPT H1/H2 within all PD. Voxel-wise differences of cerebral blood flow (CBF) values between HC, PD-CN and PD-MCI were assessed by one-way analysis of variance followed by pairwise post hoc comparisons. Further, the subgroup of PD patients carrying the risky MAPT H1/H1 haplotype was compared with noncarriers (MAPT H1/H2 haplotype) in terms of CBF by a two-sample t test. A pattern that could be summarized as "posterior hypoperfusion" (PH) differentiated the PD-MCI group from the HC group with an accuracy of 92.6% (sensitivity = 93%, specificity = 93%). Additionally, the PD patients with MAPT H1/H1 haplotype had decreased perfusion than the ones with H1/H2 haplotype at the posterior areas of the visual network (VN), default mode network (DMN), and dorsal attention network (DAN). The PH-type pattern in ASL-MRI could be employed as a biomarker of both current cognitive impairment and future cognitive decline in PD.

Do Alzheimer's Disease Patients Appear Younger than Their Real Age?

INTRODUCTION: The most prominent risk factor of Alzheimer's disease (AD) is aging. Aging also influences the physical appearance. Our clinical experience suggests that patients with AD may appear younger than their actual age. Based on this empirical observation, we set forth to test the hypothesis with human and computer-based estimation systems. METHOD: We compared 50 early-stage AD patients with 50 age and sex-matched controls. Facial images of all subjects were recorded using a video camera with high resolution, frontal view, and clear lighting. Subjects were recorded during natural conversations while performing Mini-Mental State Examination, including spontaneous smiles in addition to static images. The images were used for age estimation by 2 methods: (1) computer-based age estimation; (2) human-based age estimation. Computer-based system used a state-of-the-art deep convolutional neural network classifier to process the facial images contained in a single-video session and performed frame-based age estimation. Individuals who estimated the age by visual inspection of video sequences were chosen following a pilot selection phase. The mean error (ME) of estimations was the main end point of this study. RESULTS: There was no statistically significant difference between the ME scores for AD patients and healthy controls (p = 0.33); however, the difference was in favor of younger estimation of the AD group. The average ME score for AD patients was lower than that for healthy controls in computer-based estimation system, indicating that AD patients were on average estimated to be younger than their actual age as compared to controls. This difference was statistically significant (p = 0.007). CONCLUSION: There was a tendency for humans to estimate AD patients younger, and computer-based estimations showed that AD patients were estimated to be younger than their real age as compared to controls. The underlying mechanisms for this observation are unclear.

Patients with Lately Diagnosed Cerebrotendinous Xanthomatosis.

OBJECTIVES: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive inborn lipid storage disorder due to various pathogenic mutations in the CYP27A1 gene. Although the symptoms begin commonly in infancy, CTX diagnosis is often delayed. In this study, we report 7 Turkish CTX patients who had a delayed diagnosis despite early clinical signs and belonged to 6 unrelated families. METHODS: We have retrospectively evaluated clinical, laboratory, imaging, and genetic findings of CTX patients, which were collected from 2 centers specialized in movement disorders: the Department of Neurology, Faculty of Medicine, Istanbul University, and the Department of Neurology, Faculty of Medicine, Mersin University. RESULTS: All patients were diagnosed with CTX after neurological symptom development, and their mean age at diagnosis was 38.7 ± 9.6 years, despite a mean onset age of 12.4 ± 10.6 years. The mean follow-up period was 28 months (range: 3-60 months). The most common initial clinical abnormalities in our cohort were unexplained chronic diarrhea (42%), febrile convulsion (42%), juvenile cataract (85%), childhood depression and autism (14%), parkinsonism (14%), and intellectual disability (100%). The most prominent neurological findings were the pyramidal-cerebellar syndrome (85%) and extrapyramidal signs (42%). All patients were genetically confirmed. Serum cholestanol levels were elevated in all patients and decreased after chenodeoxycholic acid (CDCA) treatment in 6 patients. CONCLUSION: This cohort is the largest CTX case series in Turkey. All cases showed improvement in gastrointestinal symptoms as a response to CDCA treatment and stabilization on neurological symptoms, i.e., no further progression of neurological abnormalities were noted during this treatment. Therefore, early diagnosis and treatment is crucial in preventing clinical deterioration.

Adult-onset phenylketonuria with rapidly progressive dementia and parkinsonism.

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder due to mutations in the phenylalanine hydroxylase (PAH) gene, which converts phenylalanine (PHE) to tyrosine. Although it is principally a childhood disorder, in rare cases, the first signs of PKU may develop in late adulthood resembling common neurological diseases. Here we report a 59-year-old, previously normal functioning man who was admitted with blurred vision, cognitive problems, and gait difficulty that began 8 months before. He had brisk reflexes and left side dominant parkinsonism. His Mini-Mental State Examination (MMSE) score was 25/30, and neuropsychological evaluation revealed a dysexecutive syndrome with simultanagnosia and constructional apraxia. His Clinical Dementia Rating score (CDR) was 1. Cranial MRI revealed bilateral diffuse hyperintense lesions in parietal and occipital white matter in T2, fluid-attenuated inversion recovery, and diffusion weighted images. Diagnostic workup for rapidly progressive dementias was all normal except PHE level which was found to be highly elevated (1075 µmol/L, normal 39-240 µmol/L) with normal tyrosine level (61.20 µmol/L, normal 35-100 µmol/L). Three months after PHE-restricted diet, his cognitive impairment and signs of parkinsonism significantly improved, with MRI scan unchanged. This case demonstrates that late-onset PKU is a rare, treatable cause of rapidly progressive dementia and parkinsonism with certain constellations such as consanguinity and white matter abnormalities (WMAs) in imaging.

Medication management and treatment adherence in Parkinson's disease patients with mild cognitive impairment.

INTRODUCTION: The key feature that distinguishes mild cognitive impairment (MCI) from dementia is the absence of significant functional decline because of cognitive impairment. In Parkinson's disease patients (PD) with MCI (PD-MCI), the effect of cognitive impairment on complex instrumental daily activities, such as medication management, is not well established. METHOD: 26 patients with PD-MCI (diagnosed to Level 2 Movement Disorders Society diagnostic criteria) and 32 idiopathic PD patients without cognitive impairment participated in the study. A detailed neuropsychological testing battery (including tests for attention and working memory, executive functions, language, visuospatial functions, episodic memory) and various prospective memory tasks were applied to the patients. Medication taking behaviors were evaluated using two different methods based on the performance (medication management ability assessment) and self-reporting (adherence scale). RESULTS: The PD-MCI group obtained significantly lower scores in medication management assessment and made more mistakes on following prescription instructions (e.g., they took more or less tablets and did not use medications as instructed with regard to meal times). Cognitive areas predicting success in medication management performance were language, event-based prospective memory and visuospatial functions. There was no significant difference between the two groups' self-reporting of adherence. CONCLUSION: Mild cognitive impairment in patients with PD adversely affects medication management. Diagnosing MCI in PD is important to ensure that the appropriate measures can be taken to provide support and improve the medication management process. Adherence assessments based on self-reporting may not provide reliable and sensitive information in patients with PD-MCI.

Cognitive Profile in Parkinson's Disease Dementia Patients with Low versus Normal Cerebrospinal Fluid Amyloid Beta.

Introduction: In patients with Parkinson's disease (PD), low cerebrospinal fluid (CSF) amyloid beta 1-42 (Ab42) at baseline is the most consistent CSF biomarker as a risk factor for developing dementia. Low CSF Ab42 is, however, a typical hallmark of Alzheimer's disease (AD). Hence, low CSF Ab42 in patients with PD may indicate presence of comorbid AD pathology and may predict a more AD-like cognitive profile when they develop dementia. Our study aimed to investigate if low CSF Ab42 at baseline is associated with a more AD-like cognitive profile in PD patients with dementia. Methods: In a prospectively followed-up, population-based cohort of newly diagnosed PD patients, we compared the cognitive profile of dementia in those with a low CSF Ab42 level at baseline with that of patients who had normal levels at the time when they developed dementia. Four different cognitive domain z-scores (memory, attention, executive, visuospatial) were calculated. Patients were subdivided into three tertiles or categorized dichotomously based on the baseline CSF Ab42 levels as measured by electrochemiluminescence and ELISA. Results: During 10-year follow-up, 37 patients met the inclusion criteria. Memory domain composite z-scores, memory subtest z-scores, and the difference between long-delay free recall versus recognition scores were not significantly different between the groups. Composite z-scores of visuospatial functions significantly differed between the tertiles, which was not significant after Bonferroni correction. In the dichotomous group analysis, z-scores of visuospatial functions significantly differed between the two groups. The other cognitive domain z-scores were not significantly different. Conclusions: In patients with PD dementia, low CSF Ab42 level at baseline is not associated with a specific cognitive profile.

Validity and Reliability of the Pictures of Facial Affect (POFA) in Healthy People and Patients with Essential Tremor in the Turkish Population.

Introduction: This study aimed to conduct the validity and reliability of the (Pictures of Facial Affect) POFA test for the Turkish population and contribute to increasing the number of tests that are still insufficient in our country. Methods: This descriptive, randomized controlled study was conducted in two steps, namely Step 1 (Pilot Study and Validity Studies) and Step 2 (Reliability Study Step). The number of participants was planned regarding the original study by which the POFA test was developed. The EYES test was also used for comparison. In the pilot study, the most widely identified emotions from 47 of 110 photos in the POFA test were chosen as the new POFA picture set to be used in the reliability and validity study under the name "POFA Test Short Form". A total of 100 participants, including 82 healthy volunteers and 18 essential tremor (ET) patients, were enrolled in the first step of the study. Another cohort of 22 healthy volunteers was enrolled in the second step of the study for test-retest reliability analysis. Results: A significant positive correlation was found between the total POFA Test Short Form and EYES Test scores in the healthy volunteer group in terms of criterion-related validity (r=0.44, p<0.01). There were statistically significant differences between healthy volunteers and ET groups regarding EYES Total, POFA Total, POFA Sadness, POFA Anger, and POFA Neutral scores. It was observed that the 47-item POFA Test Short Form total score showed skewness and kurtosis, which demonstrated suitability for clinical use. Conclusion: The POFA Test Short Form was found to be a valid and reliable assessment tool in the Turkish population to be used in studies on emotion recognition and was shown to be beneficial for the discrimination of healthy individuals and ET patients.

The Reliability and Validity of the Turkish Version of the Survey of Activities and Fear of Falling in the Elderly.

BACKGROUND AND PURPOSE: The Survey of Activities and Fear of Falling in the Elderly (SAFE) was originally developed in English to determine the level of fear of falling and its interactions with activities of daily living. The purpose of this study was to translate and cross-culturally adapt the SAFE instrument into Turkish and investigate its psychometric properties. PARTICIPANTS: One hundred eleven older adults (72 females) with a mean age of 69 years (SD = 7.22; range, 60-87) were included. METHODS: For cross-cultural adaptation, 2 bilingual translators used the back-translation procedure. Within a 5- to 7-day period after the first assessment, the participants completed the Turkish version of the SAFE (SAFE-T) to evaluate test-retest reliability. Cronbach's α was used to assess internal consistency. The correlation with the Turkish version of the Falls Efficacy Scale-International (FES-T) was determined to check the validity. RESULTS: The SAFE-T had excellent internal consistency (α = 0.96) and test-retest reliability (intraclass correlation coefficient [ICC2,1] = 0.96 for activity level, ICC2,1 = 0.95 for fear of falling, and ICC2,1 = 0.86 for activity restriction subscales). The SAFE-T activity level and SAFE-T activity restriction subscales were moderately correlated with the FES-I (ρ = -0.51, P < .001; ρ = 0.55, P < .001, respectively). A strong positive correlation was found between the SAFE-T fear of falling subscale and the FES-I (ρ = 0.75, P < .001), indicating good concurrent validity. CONCLUSIONS: The results show that the SAFE-T is semantically and linguistically adequate to assess the fear of falling in adults older than 60 years. Excellent internal validity and test-retest reliability of the SAFE-T were defined to evaluate the fear of falling among Turkish speaking older adults.

Clinical and molecular genetic findings of hereditary Parkinson's patients from Turkey.

INTRODUCTION: The majority of Parkinson's disease (PD) ensue late-onset with a complex spectrum of environmental and genetic risk factors. Awareness of genetic causes in patients with PD is essential for genetic counseling and future genotype-oriented therapeutic developments. METHODS: Large pathogenic changes in eight PD-related genes and small pathogenic sequence variants in 22 PD-related genes were investigated simultaneously in 82 PD patients from 79 families where clinical evaluations were performed. The phenotypic characteristics of the patients with molecular changes were examined for genotype-phenotype relations. RESULTS: Pathogenic variants in SNCA, PRKN, DJ-1, FBXO7, and GBA genes were determined in 25 patients from 24 families (24/79, 30%). Associated variants were found in PRKN in 14, SNCA in three, FBXO7 in two, and DJ-1 in one patient. A novel homozygous deletion (c.491delT, p.(V164Dfs*13) (SCV001733595)) leading to protein truncation in the PRKN gene was identified in two patients from the same family. Furthermore, heterozygous GBA gene variants were detected in five patients from different families. CONCLUSION: It has been shown that the most common cause of genetically transmitted PD is the PRKN gene, while LRRK2 does not play an essential role in this selected population. It has been suggested that even if the autosomal recessive inheritance is expected, genes with autosomal dominant effects such as SNCA should not be overlooked and suggested for investigation. Our study is also the first for evaluating the pathogenic GBA variants' frequency in PD patients from Turkey.

Detection of visual and frontoparietal network perfusion deficits in Parkinson's disease dementia.

Mild cognitive impairment of Parkinson's disease (PD) may be an early manifestation that may progressively worsen to dementia. Cognitive decline has been associated with changes in the brain perfusion pattern. This study aimed to evaluate cerebral blood flow (CBF) deficits specific to different stages of cognitive decline. Seventeen patients with cognitively normal PD (PD-CN), 18 patients with PD with mild cognitive impairment (PD-MCI), and 16 patients with PD with dementia (PDD) were included in this study. The participants were scanned using a 3 T Philips MRI scanner. Arterial spin labelling magnetic resonance (ASL-MR) images were acquired, followed by calculation of the CBF maps, and registration onto the MNI152 brain atlas. A whole-brain voxel-based CBF comparison was performed among the patient groups using age as a covariate. The mean age of patients with PDD was significantly higher than that of patients with PD-MCI (P = 0.015) and PD-CN (P = 0.001). The CBF values of the three groups were significantly different in the left cuneus of the visual network (VN), left inferior frontal gyrus of the frontoparietal network (FPN), and left dorsomedial nucleus of the thalamus. PDD had lower perfusion values than PD-MCI group in the same regions detected in the main group analysis. Additionally, comparison of PDD with PD-CN and non-demented groups revealed that the perfusion reduction extended into the bilateral cuneus of the VN, bilateral thalami, and left inferior frontal gyrus of the FPN. PDD could be separated from PD-MCI and PD-CN stages with CBF deficits in non-dopaminergically mediated posterior and dopaminergically mediated frontal networks.

Neuroinflammation Mediators are Reduced in Sera of Parkinson's Disease Patients with Mild Cognitive Impairment.

INTRODUCTION: Cognitive impairment is common in Parkinson's disease (PD) and PD patients with mild cognitive impairment (PD-MCI) are at increased risk of developing Parkinson's disease dementia (PDD). Reliable biomarkers are required for objective identification of cognitive decline in PD. In this pilot study, serum levels of well-known mediators of neuroinflammation were measured in PD patients with or without MCI to find out the involvement of neuroinflammation and microglial activation in PD-MCI. METHODS: 36 PD-MCI, 25 PD patients with normal cognition (PD-NC) and 19 healthy controls were recruited. Serum levels of NLR family pyrin domain containing 1 (NLRP1), NLRP3, caspase-1, NF-kB, IL-1b and IL-18 were measured by ELISA and a panel of neuropsychological tests was administered. RESULTS: PD-MCI patients showed significantly reduced levels of NF-kB, IL-1b and IL-18, whereas NLRP1, NLRP3 and caspase-1 levels were comparable among PD-NC and PD-MCI patients. IL-18 levels were positively correlated with Addenbrooke's Cognitive Examination-Revised and Symbol Digit Modalities Test scores. CONCLUSION: Levels of several microglial activation mediators are reduced in PD-MCI patients inferring a protective role to certain inflammation factors against cognitive decline in PD.

Peripheral GRN mRNA and Serum Progranulin Levels as a Potential Indicator for Both the Presence of Splice Site Mutations and Individuals at Risk for Frontotemporal Dementia.

Progranulin (GRN) gene mutations are a major cause of frontotemporal dementia (FTD). Most mutations identified to date are null mutations, which are predicted to cause the pathology via haploinsufficiency. Decreased peripheral progranulin protein (PGRN) levels are associated with the presence of GRN null mutations and are accepted as reliable biomarkers. In this study, our aim was to test whether the presence of specific GRN splice site mutations (c.- 8+2T>G and c.708+6_9del), could be predicted by peripheral mRNA or protein GRN levels, by studying affected and asymptomatic individuals from FTD families. We also tested four missense GRN variants to assess if altered GRN levels depended on the type of mutation.Our results confirmed a reduction in both mRNA and protein PGRN levels in the splice site mutation carriers, which is consistent with previous reports for null mutations. Our results also suggested that both decreased peripheral GRN mRNA and serum PGRN levels indicate the presence of pathogenic mutations in affected individuals, and identify the asymptomatic individuals at risk, without previous knowledge of genetic status. Both inferences suggest a potential use of peripheral GRN mRNA or serum PGRN levels as biomarkers for families with FTD.

Late-onset phenotype associated with a homozygous GJC2 missense mutation in a Turkish family.

OBJECTIVE: Recessive mutations in the Gap Junction Protein Gamma 2 (GJC2) gene cause Pelizaeus-Merzbacher-like disease type 1, a severe infantile-onset hypomyelinating leukodystrophy. Milder, late-onset phenotypes including complicated spastic paraplegia in one family (SPG44), and mild tremor in one case, were reported associated to GJC2 homozygous missense mutations. Here, we report a new family with two siblings carrying a different homozygous GJC2 mutation, presenting with late-onset ataxic and pyramidal disturbances, and parkinsonism in one of them. METHODS: Two affected siblings were studied by neurological examination and brain MRI. Genetic analyses included genome-wide homozygosity mapping in both siblings, and whole exome sequencing in one sib. The resulting candidate gene variant was validated by Sanger sequencing. RESULTS: The affected siblings share a novel homozygous GJC2 missense mutation (c.820G>C, p.Val274Leu), predicted as pathogenic by all used in-silico tools. Brain MRI showed hyperintense signal in T2-weighted images in the internal capsule and subcortical and periventricular white matter, consistent with hypomyelination. CONCLUSIONS: Our findings confirm and further expand the late-onset phenotypes of GJC2 mutations, to include prominent ataxia, pyramidal disturbances and mild parkinsonism, and confirm the distinctive associated MRI pattern.