CSF levels of synaptosomal-associated protein 25 and synaptotagmin-1 in first-episode psychosis subjects.

Post-mortem studies consistently show evidence of reduced synaptic protein levels in patients with schizophrenia. Clinically high-risk subjects show a steeper decrease in grey matter thickness and in vitro modeling using patient-derived cells implicate excessive synaptic pruning during neurodevelopment as a part of the schizophrenia pathophysiology. However, it is unclear to what extent synapse elimination is present during various stages of the disease, which is of clinical importance as in a real-world setting most subjects received their first-episode psychosis (FEP) diagnosis not until their mid-twenties. In the present study, we measured cerebrospinal fluid (CSF) concentrations of the two pre-synaptic proteins synaptosomal-associated protein 25 (SNAP-25) and synaptotagmin-1 (SYT-1), both of which are increased in conditions of ongoing synaptic degeneration, in 44 FEP subjects (mean age 29.9 years) and 21 healthy controls (25.9 years) using immunoprecipitation mass spectrometry. Neither protein was found to differ between healthy controls and patients, and they showed no correlation with symptom ratings, cognitive performance or antipsychotic medication. Additional studies in high-risk subjects in the early prodromal phase will be needed to address if excessive synapse destruction occurs before the development of overt psychotic symptoms.

Swedish Version of the Hayling Test: Clinical Utility in Frontotemporal Dementia Syndromes.

OBJECTIVES: The aim of this study was to assess the psychometric properties of a Swedish version of the Hayling test (HT-S) and its clinical utility in a group of patients with different frontotemporal dementia (FTD) syndromes. Early diagnosis of FTD is a challenge and requires a broad arsenal of assessment methods, neuropsychological tests not the least. The Hayling test assesses executive functions including initiation, efficiency and response inhibition. METHODS: Seventy-six healthy controls were included as well as patients with the behavioral variant FTD (bvFTD; n = 17), semantic dementia (SD, n = 6), and progressive supranuclear palsy (n = 12). The Color Word Interference Test was administered to examine the construct validity. RESULTS: Age showed a correlation with better performances in younger participants whereas the importance of sex and education were less evident. The split half reliability and internal consistency were equal to, or better, than reported for the original version. The interrater reliability was excellent. The construct validity was supported, nevertheless indicating partly different processes behind the performances of the two tests. The FTD group performed significantly worse than healthy controls on efficiency and response inhibition and there were also significant differences in performances between the syndromes despite small samples. CONCLUSIONS: The psychometric properties and clinical utility of the Swedish version are satisfactory for measuring efficiency and response inhibition with results indicating dissimilar profiles in the performances in the different syndromes. These results need to be corroborated in larger samples. (JINS, 2019, 25, 195-203).

Grey and White Matter Clinico-Anatomical Correlates of Disinhibition in Neurodegenerative Disease.

Disinhibition is an important symptom in neurodegenerative diseases. However, the clinico-anatomical underpinnings remain controversial. We explored the anatomical correlates of disinhibition in neurodegenerative disease using the perspective of grey and white matter imaging. Disinhibition was assessed with a neuropsychological test and a caregiver information-based clinical rating scale in 21 patients with prefrontal syndromes due to behavioural variant frontotemporal dementia (n = 12) or progressive supranuclear palsy (n = 9), and healthy controls (n = 25). Cortical thickness was assessed using the Freesurfer software on 3T MRI data. The integrity of selected white matter tracts was determined by the fractional anisotropy (FA) from Diffusion Tensor Imaging. Disinhibition correlated with the cortical thickness of the right parahippocampal gyrus, right orbitofrontal cortex and right insula and the FA of the right uncinate fasciculus and right anterior cingulum. Notably, no relationship was seen with the thickness of ventromedial prefrontal cortex. Our results support an associative model of inhibitory control, distributed in a medial temporal lobe-insular-orbitofrontal network, connected by the intercommunicating white matter tracts. This reconciles some of the divergences among previous studies, but also questions the current conceptualisation of the "prefrontal" syndrome and the central role attributed to the ventromedial prefrontal cortex in inhibitory control.

Striatal Atrophy in the Behavioural Variant of Frontotemporal Dementia: Correlation with Diagnosis, Negative Symptoms and Disease Severity.

INTRODUCTION: Behavioural variant frontotemporal dementia (bvFTD) is associated with changes in dorsal striatal parts of the basal ganglia (caudate nucleus and putamen), related to dysfunction in the cortico-striato-thalamic circuits which help mediate executive and motor functions. We aimed to determine whether the size and shape of striatal structures correlated with diagnosis of bvFTD, and measures of clinical severity, behaviour and cognition. MATERIALS AND METHODS: Magnetic resonance imaging scans from 28 patients with bvFTD and 26 healthy controls were manually traced using image analysis software (ITK-SNAP). The resulting 3-D objects underwent volumetric analysis and shape analysis, through spherical harmonic description with point distribution models (SPHARM-PDM). Correlations with size and shape were sought with clinical measures in the bvTFD group, including Frontal Behavioural Inventory, Clinical Dementia Rating for bvFTD, Color Word Interference, Hayling part B and Brixton tests, and Trail-Making Test. RESULTS: Caudate nuclei and putamina were significantly smaller in the bvFTD group compared to controls (left caudate 16% smaller, partial eta squared 0.173, p=0.003; right caudate 11% smaller, partial eta squared 0.103, p=0.023; left putamen 18% smaller, partial eta squared 0.179, p=0.002; right putamen 12% smaller, partial eta squared 0.081, p=0.045), with global shape deflation in the caudate bilaterally but no localised shape change in putamen. In the bvFTD group, shape deflations on the left, corresponding to afferent connections from dorsolateral prefrontal mediofrontal/anterior cingulate and orbitofrontal cortex, correlated with worsening disease severity. Global shape deflation in the putamen correlated with Frontal Behavioural Inventory scores-higher scoring on negative symptoms was associated with the left putamen, while positive symptoms were associated with the right. Other cognitive tests had poor completion rates. CONCLUSION: Behavioural symptoms and severity of bvFTD are correlated with abnormalities in striatal size and shape. This adds to the promise of imaging the striatum as a biomarker in this disease.

Somatic complaints in frontotemporal dementia.

Frontotemporal dementia (FTD) is associated with a broad spectrum of clinical characteristics. The objective of this study was to analyze the prevalence of unexplained somatic complaints in neuropathologically verified FTD. We also examined whether the somatic presentations correlated with protein pathology or regional brain pathology and if the patients with these somatic features showed more depressive traits. Ninety-seven consecutively neuropathologically verified FTLD patients were selected. All 97 patients were part of a longitudinal study of FTD and all medical records were systematically reviewed. The somatic complaints focused on were headache, musculoskeletal, gastro/urogenital and abnormal pain response. Symptoms of somatic character (either somatic complaints and/or abnormal pain response) were found in 40.2%. These patients did not differ from the total group with regard to gender, age at onset or duration. Six patients showed exaggerated reactions to sensory stimuli, whereas three patients showed reduced response to pain. Depressive traits were present in 38% and did not correlate with somatic complaints. Suicidal behavior was present in 17 patients, in 10 of these suicidal behavior was concurrent with somatic complaints. No clear correlation between somatic complaints and brain protein pathology, regional pathology or asymmetric hemispherical atrophy was found. Our results show that many FTD patients suffer from unexplained somatic complaints before and/or during dementia where no clear correlation can be found with protein pathology or regional degeneration. Somatic complaints are not covered by current diagnostic criteria for FTD, but need to be considered in diagnostics and care. The need for prospective studies with neuropathological follow up must be stressed as these phenomena remain unexplained, misinterpreted, bizarre and, in many cases, excruciating.

Diffusion tensor tractography versus volumetric imaging in the diagnosis of behavioral variant frontotemporal dementia.

MRI diffusion tensor imaging (DTI) studies of white matter integrity in behavioral variant frontotemporal dementia have consistently shown involvement of frontal and temporal white matter, corresponding to regional loss of cortical volume. Volumetric imaging has a suboptimal sensitivity as a diagnostic tool and thus we wanted to explore if DTI is a better method to discriminate patients and controls than volumetric imaging. We examined the anterior cingulum bundle in 14 patients with behavioral variant frontotemporal dementia and 22 healthy controls using deterministic manual diffusion tensor tractography, and compared DTI parameters with two measures of cortical atrophy, VBM and cortical thickness, of the anterior cingulate cortex (ACC). Statistically significant changes between patients and controls were detected in all DTI parameters, with large effect sizes. ROC-AUC was for the best DTI parameters: 0.92 (fractional anisotropy) to 0.97 (radial diffusivity), 0.82 for the best cortical parameter, VBM of the ACC. Results from the AUC were confirmed with binary logistic regression analysis including demographic variables, but only for fractional anisotropy and mean diffusivity. Ability to classify patient/nonpatient status was significantly better for mean diffusivity vs. VBM (p=0.031), and borderline significant for fractional anisotropy vs. VBM (p=0.062). The results indicate that DTI could offer advantages in comparison with the assessment of cortical volume in differentiating patients with behavioral variant frontotemporal dementia and controls.

In vivo imaging of astrocytosis in Alzheimer's disease: an ¹¹C-L-deuteriodeprenyl and PIB PET study.

PURPOSE: Astrocytosis is an important feature of the neuropathology of Alzheimer's disease (AD), yet there is currently no way of detecting this phenomenon in vivo. METHODS: In this study we examine the retention of the positron emission tomography (PET) tracer (11)C-L-deuteriodeprenyl (DED), thought to bind activated astrocytes, in 9 patients with moderate to severe AD compared with 11 healthy controls. As a measure of amyloid load, (11)C-labelled Pittsburgh Compound B (PIB) retention was determined. RESULTS: Results show a significantly higher (11)C-L-DED retention in the frontal (35.1% increase, p = 0.001), parietal (35.2%, p = 0.001), temporal (30.9%, p = 0.0001) and medial temporal lobes (22.3%, p = 0.001) in AD compared to healthy controls after blood flow correction. DED retention in the sensorimotor and occipital cortices, and in white matter and subcortical structures, did not differ between groups. There was a moderate but statistically significant (r = 0.492, p = 0.01) correlation between DED and PIB retention values. CONCLUSION: Our conclusion is that DED may serve as an in vivo marker for astrocytosis in AD, providing a window into intermediate processes between amyloidosis and neuronal loss and a means of monitoring immunotherapy.

Frontotemporal dementia-amyotrophic lateral sclerosis complex is simulated by neurodegeneration with brain iron accumulation.

We describe a case of late onset neurodegeneration with brain iron accumulation (NBIA) presenting as frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS). A male patient presented at age 66 with change of personality: disinhibition, emotional blunting, and socially inappropriate behavior, coupled with dysarthria, dystonia, and corticospinal tract involvement. Magnetic resonance imaging showed general cortical atrophy, iron deposits in the globus pallidus, and the "eye of the tiger" sign. Neuropsychologic performance was globally reduced, especially executive functions. Fluorodeoxyglucose positron emission tomography showed hypometabolism predominantly in frontal and temporal areas. Repeated neurophysiologic examinations showed signs of chronic denervation. The patient was diagnosed with NBIA but fulfilled consensus criteria for FTD and had a clinical picture of ALS, without neurophysiologic confirmation. Our finding introduces NBIA as a possible cause of FTD and as a differential diagnosis of the FTD-ALS complex.

In vivo amyloid imaging with PET in frontotemporal dementia.

BACKGROUND: N-methyl[11C]2-(4'methylaminophenyl)-6-hydroxy-benzothiazole (PIB) is a positron emission tomography (PET) tracer with amyloid binding properties which allows in vivo measurement of cerebral amyloid load in Alzheimer's disease (AD). Frontotemporal dementia (FTD) is a syndrome that can be clinically difficult to distinguish from AD, but in FTD amyloid deposition is not a characteristic pathological finding. PURPOSE: The aim of this study is to investigate PIB retention in FTD. METHODS: Ten patients with the diagnosis of FTD participated. The diagnosis was based on clinical and neuropsychological examination, computed tomography or magnetic resonance imaging scan, and PET with 18 Fluoro-2-deoxy-d-glucose (FDG). The PIB retention, measured in regions of interest, was normalised to a reference region (cerebellum). The results were compared with PIB retention data previously obtained from 17 AD patients with positive PIB retention and eight healthy controls (HC) with negative PIB retention. Statistical analysis was performed with a students t-test with significance level set to 0.00625 after Bonferroni correction. RESULTS: Eight FTD patients showed significantly lower PIB retention compared to AD in frontal (p < 0.0001), parietal (p < 0.0001), temporal (p = 0.0001), and occipital (p = 0.0003) cortices as well as in putamina (p < 0.0001). The PIB uptake in these FTD patients did not differ significantly from the HC in any region. However, two of the 10 FTD patients showed PIB retention similar to AD patients. CONCLUSION: The majority of FTD patients displayed no PIB retention. Thus, PIB could potentially aid in differentiating between FTD and AD.