Treatable Vascular Risk and Cognitive Performance in Persons Aged 35 Years or Older:Longitudinal Study of Six Years

BACKGROUND: Poor cognitive performance is associated with high vascular risk. However, this association is only investigated in elderly. As neuropathological changes precede clinical symptoms of cognitive impairment by several decades, it is likely that cognitive performance is already associated with vascular risk at middle-age. OBJECTIVES: To investigate the association of cognitive performance with treatable vascular risk in middle-aged and old persons. DESIGN: Longitudinal study with three measurements during follow-up period of 5.5 years. SETTING: City of Groningen, the Netherlands. PARTICIPANTS: Cohort of 3,572 participants (age range, 35-82 years; mean age, 54 years; men, 52%). EXPOSURE: Treatable vascular risk as defined by treatable components of the Framingham Risk Score for Cardiovascular Disease at the first measurement (diabetes mellitus, smoking, hypercholesterolemia and hypertension). MEASUREMENTS: Change in cognitive performance during follow-up. Cognitive performance was measured with Ruff Figural Fluency Test (RFFT) and Visual Association Test (VAT), and calculated as the average of the standardized RFFT and VAT score per participant. RESULTS: The mean (SD) cognitive performance changed from 0.00 (0.79) at the first measurement to 0.15 (0.83) at second measurement and to 0.39 (0.82) at the third measurement (Ptrend CONCLUSIONS: Change in cognitive performance was associated with treatable vascular risk in persons aged 35 years or older

Agreement between Computerized and Human Assessment of Performance on the Ruff Figural Fluency Test

The Ruff Figural Fluency Test (RFFT) is a sensitive test for nonverbal fluency suitable for all age groups. However, assessment of performance on the RFFT is time-consuming and may be affected by interrater differences. Therefore, we developed computer software specifically designed to analyze performance on the RFFT by automated pattern recognition. The aim of this study was to compare assessment by the new software with conventional assessment by human raters. The software was developed using data from the Lifelines Cohort Study and validated in an independent cohort of the Prevention of Renal and Vascular End Stage Disease (PREVEND) study. The total study population included 1,761 persons: 54% men; mean age (SD), 58 (10) years. All RFFT protocols were assessed by the new software and two independent human raters (criterion standard). The mean number of unique designs (SD) was 81 (29) and the median number of perseverative errors (interquartile range) was 9 (4 to 16). The intraclass correlation coefficient (ICC) between the computerized and human assessment was 0.994 (95%CI, 0.988 to 0.996; p<0.001) and 0.991 (95%CI, 0.990 to 0.991; p<0.001) for the number of unique designs and perseverative errors, respectively. The mean difference (SD) between the computerized and human assessment was -1.42 (2.78) and +0.02 (1.94) points for the number of unique designs and perseverative errors, respectively. This was comparable to the agreement between two independent human assessments: ICC, 0.995 (0.994 to 0.995; p<0.001) and 0.985 (0.982 to 0.988; p<0.001), and mean difference (SD), -0.44 (2.98) and +0.56 (2.36) points for the number of unique designs and perseverative errors, respectively. We conclude that the agreement between the computerized and human assessment was very high and comparable to the agreement between two independent human assessments. Therefore, the software is an accurate tool for the assessment of performance on the RFFT

Cytoplasmic Accumulation and Aggregation of TDP-43 upon Proteasome Inhibition in Cultured Neurons

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by intraneuronal deposition of the nuclear TAR DNA-binding protein 43 (TDP-43) caused by unknown mechanisms. Here, we studied TDP-43 in primary neurons under different stress conditions and found that only proteasome inhibition by MG-132 or lactacystin could induce significant cytoplasmic accumulation of TDP-43, a histopathological hallmark in disease. This cytoplasmic accumulation was accompanied by phosphorylation, ubiquitination and aggregation of TDP-43, recapitulating major features of disease. Proteasome inhibition produced similar effects in both hippocampal and cortical neurons, as well as in immortalized motor neurons. To determine the contribution of TDP-43 to cell death, we reduced TDP-43 expression using small interfering RNA (siRNA), and found that reduced levels of TDP-43 dose-dependently rendered neurons more vulnerable to MG-132. Taken together, our data suggests a role for the proteasome in subcellular localization of TDP-43, and possibly in disease

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

Lithium is a first-line therapy for bipolar affective disorder. However, various adverse effects, including a Parkinson-like hand tremor, often limit its use. The understanding of the neurobiological basis of these side effects is still very limited. Nigral iron elevation is also a feature of Parkinsonian degeneration that may be related to soluble tau reduction. We found that magnetic resonance imaging T2 relaxation time changes in subjects commenced on lithium therapy were consistent with iron elevation. In mice, lithium treatment lowers brain tau levels and increases nigral and cortical iron elevation that is closely associated with neurodegeneration, cognitive loss and parkinsonian features. In neuronal cultures lithium attenuates iron efflux by lowering tau protein that traffics amyloid precursor protein to facilitate iron efflux. Thus, tau- and amyloid protein precursor-knockout mice were protected against lithium-induced iron elevation and neurotoxicity. These findings challenge the appropriateness of lithium as a potential treatment for disorders where brain iron is elevated (for example, Alzheimer’s disease), and may explain lithium-associated motor symptoms in susceptible patients

Tau-Mediated Nuclear Depletion and Cytoplasmic Accumulation of SFPQ in Alzheimer's and Pick's Disease

Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Here, we performed an unbiased SAGE (serial analysis of gene expression) of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD), and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions

Tau exacerbates excitotoxic brain damage in an animal model of stroke

10.1038/s41467-017-00618-0Nature Communications8147

Tau exacerbates excitotoxic brain damage in an animal model of stroke

Neuronal excitotoxicity induced by aberrant excitation of glutamatergic receptors contributes to brain damage in stroke. Here we show that tau-deficient (tau-/-) mice are profoundly protected from excitotoxic brain damage and neurological deficits following experimental stroke, using a middle cerebral artery occlusion with reperfusion model. Mechanistically, we show that this protection is due to site-specific inhibition of glutamate-induced and Ras/ERK-mediated toxicity by accumulation of Ras-inhibiting SynGAP1, which resides in a post-synaptic complex with tau. Accordingly, reducing SynGAP1 levels in tau-/- mice abolished the protection from pharmacologically induced excitotoxicity and middle cerebral artery occlusion-induced brain damage. Conversely, over-expression of SynGAP1 prevented excitotoxic ERK activation in wild-type neurons. Our findings suggest that tau mediates excitotoxic Ras/ERK signaling by controlling post-synaptic compartmentalization of SynGAP1.Excitotoxicity contributes to neuronal injury following stroke. Here the authors show that tau promotes excitotoxicity by a post-synaptic mechanism, involving site-specific control of ERK activation, in a mouse model of stroke