Serum neurofilament light chain in behavioral variant frontotemporal dementia.

OBJECTIVE: To determine the association of serum neurofilament light chain (NfL) with functional deterioration and brain atrophy during follow-up of patients with behavioral variant frontotemporal dementia (bvFTD). METHODS: Blood NfL levels from 74 patients with bvFTD, 26 with Alzheimer disease (AD), 17 with mild cognitive impairment (MCI), and 15 healthy controls (Con) at baseline and follow-up were determined and analyzed for the diagnostic potential in relation to functional assessment (Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB], frontotemporal lobar degeneration-related CDR-SOB, Mini-Mental State Examination [MMSE]) and brain volumetry. RESULTS: At baseline, serum NfL level correlated with CSF NfL (bvFTD r = 0.706, p < 0.0001; AD/MCI r = 0.666, p = 0.0003). Highest serum levels were observed in bvFTD (p <0 0.0001 vs Con and MCI, p = 0.0078 vs AD, respectively). Discrimination of bvFTD from Con/MCI/AD was possible with 91%/74%/74% sensitivity and 79%/74%/58% specificity. At follow-up, serum NfL increased in bvFTD and AD (p = 0.0039 and p = 0.0006, respectively). At baseline and follow-up, NfL correlated with functional scores of patients with bvFTD (e.g., CDR-SOB [baseline] r = 0.4157, p = 0.0006; [follow-up] r = 0.5629, p < 0.0001) and with atrophy in the gray and white matter of many brain regions including frontal and subcortical areas (e.g., frontal lobe: r = -0.5857, p < 0.0001; 95% confidence interval -0.7415 to -0.3701). For patients with AD/MCI, NfL correlated with the functional performance as well (e.g., CDR-SOB [baseline] r = 0.6624, p < 0.0001; [follow-up] r = 0.5659, p = 0.0003) but not with regional brain volumes. CONCLUSIONS: As serum NfL correlates with functional impairment and brain atrophy in bvFTD at different disease stages, we propose it as marker of disease severity, paving the way for its future use as outcome measure for clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with cognitive problems, serum NfL concentration discriminates bvFTD from other forms of dementia.

Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression.

OBJECTIVES: Neurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mechanisms might help in diagnosis, staging and prediction of outcome. We aimed at determining the origin and differential diagnostic and prognostic potential of the putative marker of microglial activation chitotriosidase (CHIT1). METHODS: Altogether 316 patients were included, comprising patients with sporadic ALS, ALS mimics (disease controls (DCo)), frontotemporal lobar degeneration (FTLD), Creutzfeldt-Jakob disease (CJD), Alzheimer's disease (AD), Parkinson's disease (PD) and healthy controls (Con). CHIT1 and neurofilament levels were determined in cerebrospinal fluid (CSF) and blood and analysed with regard to diagnostic sensitivity and specificity and prognostic performance. Additionally, postmortem tissue was analysed for CHIT1 expression. RESULTS: In ALS, CHIT1 CSF levels were higher compared with Con (p<0.0001), DCo (p<0.05) and neurodegenerative diseases (AD p<0.05, PD p<0.01, FTLD p<0.0001) except CJD. CHIT1 concentrations were correlated with ALS disease progression and severity but not with the survival time, as did neurofilaments. Serum CHIT1 levels were not different in ALS compared with any other study group. In the spinal cord of patients with ALS, but not Con, AD or CJD cases, CHIT1 was expressed in the corticospinal tract and CHIT1 staining colocalised with markers of microglia (IBA1) and macrophages (CD68). CONCLUSIONS: CHIT1 concentrations in the CSF of patients with ALS may reflect the extent of microglia/macrophage activation in the white matter of the spinal cord. CHIT1 could be a potentially useful marker for differential diagnosis and prediction of disease progression in ALS and, therefore, seems suitable as a supplemental marker for patient stratification in therapeutic trials.

Neurofilament as a blood marker for diagnosis and monitoring of primary progressive aphasias.

OBJECTIVE: To assess the utility of serum neurofilament for diagnosis and monitoring of primary progressive aphasia (PPA) variants. METHODS: We investigated neurofilament light chain (NF-L) levels in blood of 99 patients with PPA (40 with nonfluent variant PPA [nfvPPA], 38 with semantic variant PPA [svPPA], 21 with logopenic variant PPA [lvPPA]) and compared diagnostic performance with that reached by CSF NF-L, phosphorylated neurofilament heavy chain (pNF-H), ß-amyloid (Aß1-42), tau, and phosphorylated tau. The longitudinal change of blood NF-L levels was measured and analyzed for correlation with functional decline and brain atrophy. RESULTS: Serum NF-L is increased in PPA compared to controls and discriminates between nfvPPA/svPPA and lvPPA with 81% sensitivity and 67% specificity (cutoff 31 pg/mL). CSF NF-L, pNF-H, tau, phosphorylated tau, and Aß1-42 achieved similar performance, and pNF-H was the only marker for discrimination of nfvPPA from svPPA/lvPPA. In most patients with nfvPPA and svPPA, but not lvPPA, serum NF-L increased within follow-up. The increase correlated with functional decline and progression of atrophy of the left frontal lobe of all patients with PPAs and the right middle frontal gyrus of patients with nfvPPA and svPPA. CONCLUSIONS: Blood level of NF-L can aid the differential diagnosis of PPA variants, especially in combination with CSF pNF-H. Because serum NF-L correlates with functional decline and atrophy in the disease course, it qualifies as an objective disease status marker. Extended follow-up studies with cases of known neuropathology are imperative. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with PPA, blood levels of NF-L can distinguish the logopenic variant from the nonfluent/agrammatic and semantic variants.

No association of common VCP variants with sporadic frontotemporal dementia.

Mutations in the gene for valosin containing protein (VCP) cause autosomal dominant inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD). To investigate the role of this novel gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 27 single nucleotide polymorphisms covering the entire VCP genomic region in 198 patients with sporadic FTD and 184 matched controls from Germany. No significant association could be demonstrated. There is no evidence, that common variants in VCP confer a strong risk to the development of sporadic FTD.

No association of TDP-43 with sporadic frontotemporal dementia.

A hyperphosphorylated, ubiquitinated form of TDP-43, known as pathologic TDP-43, was shown to be a central component of ubiquitin-positive, tau-negative and alpha-synuclein-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amytrophic lateral sclerosis (ALS). To investigate the role of the TDP-43 gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 10 single nucleotide polymorphisms covering the entire TDP-43 genomic region, including the MASP2 gene in 173 patients with sporadic FTD (including 7 patients that were diagnosed with FTD and ALS) and 184 matched controls from Germany. Although we could observe a weak trend towards a potential disease association in a few FTD/ALS patients, no significant association with sporadic FTD could be demonstrated. There is no evidence, that common variants in TDP-43 confer a strong risk to the development of sporadic FTD.

["Homo neurobiologicus"--anthropological concepts in modern psychiatry]. / Homo neurobiologicus--Menschenbilder in der modernen Psychiatrie.

The workings of the human brain can now be studied with a large arsenal of modern technical tools which lead us far beyond traditional realms of philosophical self-reflection and conventional experimental psychology. The black box of the human mind has become illuminated with the following consequences: (1) diagnosis and monitoring of mental and neurological diseases have improved significantly; and (2) early interpretations of the brain's workings as we can now see it, influence the way we think and feel about ourselves. They form an inevitable part of modern anthropology, particularly in its applied forms, e.g. psychiatry and psychotherapy. Conservative branches of human studies may be appalled by nimble neuroscientists who suddenly claim superior evidence and authority. It is an open question whether these schools of traditional and of revolutionary data acquisition and thought will find a common language which can also be translated into clinically useful concepts.

Pest controllers: a high-risk group for Multiple Chemical Sensitivity (MCS)?

INTRODUCTION: Based on the assumption that professional groups with frequent chemical exposure are at an increased risk for developing Multiple Chemical Sensitivity (MCS), a sample of 45 professional pest controllers was investigated. METHODS: The examination of the pest controllers consisted of a physical and laboratory examination with urine screening for pyrethroid metabolites, a psychiatric interview, a neuropsychological test battery, and a chemical sensitivity questionnaire. RESULTS: Persistent or serious work related health problems and chemical sensitivity were not reported. In urine, cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (Br(2)CA) was detected in 11%, 4-fluoro-3-phenoxybenzoic acid (F-PBA) in 7%. 3-phenoxybenzoic acid (3-PBA) exceeded the reference range in 9%, cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid (Cl(2)CA) in 20%. Increased liver enzymes and blood count deviations were rather common. 38% had psychiatric disorders. With few exceptions, neuropsychological testing results were normal. CONCLUSIONS: The results do not support the hypothesis that work-related insecticide exposure promotes chemical sensitivity.

The Ekman 60 Faces Test as a diagnostic instrument in frontotemporal dementia.

Frontotemporal dementia (FTD) is characterized by dramatic changes of personality and behaviour. Impaired ability of emotional processing could contribute to these symptoms, as it may lead to misinterpretation of emotional cues that would normally guide behaviour. The aim of the present study was to investigate if the Ekman 60 Faces Test, an instrument to test the recognition of basic facial emotions, enables the differentiation between patients with mild FTD and cognitively healthy subjects (HC). We found that compared to 33 cognitively healthy subjects, 25 patients with mild FTD were impaired in the recognition of basic emotions. At a cut-off score from 46 out of 60 points, the Ekman 60 Faces Test discriminated between patients with mild FTD and HC with 97% diagnostic accuracy (sensitivity: 94%; specificity: 100%). The results of the present study were consistent with the findings of prior studies on smaller patient samples.

Distúrbio do metabolismo de fosfolípides na doença de Alzheimer / Disordered metabolism of membrane phospholipds in Alzheimer's disease

A fosfolipase A2 (PLA2) é uma enzima fundamental no metabolismo dos fosfolípides da membrana celular. A PLA2 influencia o processamento e a secreção da proteína precursora do amilóide, que dá origem ao peptídeo ß-amilóide, o componente principal das placas senis na doença de Alzheimer (DA). Investigamos a atividade da PLA2 em duas amostras: a) num estudo post mortem, em tecido cerebral de 23 pacientes com uma DA e 20 controles não-dementes, e b) em plaquetas de 16 pacientes com uma DA provável, 13 controles sadios e 14 pacientes idosos com uma depressão. No cérebro, a atividade da PLA2 estava significantemente reduzida no córtex parietal e frontal de pacientes com DA. Esta redução estava correlacionada com um início precoce da doença, com um número mais elevado de neurofibrilas e placas senis, e com um óbito mais prematuro. Também nas plaquetas de pacientes com DA encontramos uma redução da atividade da PLA2 em comparação com os controles sadios e deprimidos. A redução da atividade da enzima em plaquetas estava correlacionada com um início precoce da doença, com o grau de atrofia cerebral e com um déficit cognitivo mais acentuado, indicando assim uma relação entre a redução da PLA2 e uma forma mais severa da doença. Nossos resultados indicam um distúrbio do metabolismo de fosfolípides na DA e sugerem que a redução da atividade da PLA2 poderia contribuir para a formação do peptídeo ß-amilóide na doença. Estudos futuros devem esclarecer se a atividade da PLA2 em plaquetas poderia ser útil como um marcador periférico para a DA, ou como preditor para o grau de severidade da doença

Disturbios do matabolismo de fosfolipides na doenca de Alzheimer

A fosfolipase A2 (PLA2) e uma enzima fundamental no metabolismo dos fosfolipides da membrana celular. A PLA2 influencia o processamento e a secrecao da proteina precursora do amiloide, que da origem ao peptideo beta-amiloide, o componente principal das placas senis na doenca de Alzheimer (DA). Investigamos a atividade da PLA2 em duas amostras: a) num estudo post mortem, em tecido cerebral de 23 pacientes com uma DA e 20 controles nao-dementes, e b) em plaquetas de 16 pacientes com uma DA provavel, 13 controles sadios e 14 pacientes idosos com uma depressao. No cerebro, a atividade da PLA2 estava significantemente reduzida no cortex parietal e frontal de pacientes com DA. Esta reducao estava correlacionada com um inicio precoce da doenca, com um numero mais elevado de neurofibrilas e placas senis, e com um obito mais prematuro. Tambem nas plaquetas de pacientes com DA encontramos uma reducao da atividade da PLA2 em comparacao com os controles sadios e deprimidos. A reducao da atividade da enzima em plaquetas estava correlacionada com um inicio precoce da doenca, com o grau de atrofia cerebral e com um deficit cognitivo mais acentuado, indicando assim uma relacao entre a reducao da PLA2 e uma forma mais severa da doenca. Nossos resultados indicam um disturbio do metabolismo de fosfolipides na DA e sugerem que a reducao da atividade da PLA2 poderia contribuir para a formacao do peptideo beta-amiloide na doenca. Estudos futuros devem esclarecer se a atividade da PLA2 em plaquetas poderia ser util como um marcador periferico para a DA, ou como preditor para o grau de severidade da doenca.