Early brainstem [18F]THK5351 uptake is linked to cortical hyper-excitability in healthy aging

BACKGROUND: Neuronal hyper-excitability characterizes the early stages of Alzheimer's disease (AD). In animals, early misfolded tau and amyloid-beta (Aβ) protein accumulation, both central to AD neuropathology, promote cortical excitability and neuronal network dysfunction. In healthy humans, misfolded tau and Aβ aggregates are first detected, respectively, in the brainstem and frontomedial and temporobasal cortices, decades prior to the onset of AD cognitive symptoms. Whether cortical excitability is related to early brainstem tau, and its associated neuroinflammation, and cortical Aβ aggregations remains unknown. METHODS: We probed frontal cortex excitability, using transcranial magnetic stimulation combined with electroencephalography, in a sample of 64 healthy late middle-aged individuals (50-69 y; 45 women). We assessed whole-brain [18F]THK5351 positron emission tomography (PET) uptake as a proxy measure of tau/neuroinflammation, and whole-brain Aβ burden with [18F]Flutemetamol or [18F]Florbetapir radiotracers. RESULTS: We find that higher [18F]THK5351 uptake in a brainstem monoaminergic compartment is associated with increased cortical excitability (r = .29, p = .02). By contrast, [18F]THK5351 PET signal in the hippocampal formation, although strongly correlated with brainstem signal in whole-brain voxel-based quantification analyses (pFWE-corrected < .001), was not significantly associated with cortical excitability (r = .14, p = .25). Importantly, no significant association was found between early Aβ cortical deposits and cortical excitability (r = -.20, p = .11). CONCLUSION: These findings reveal potential brain substrates for increased cortical excitability in preclinical AD and may constitute functional in vivo correlates of early brainstem tau accumulation and neuroinflammation in humans. TRIAL REGISTRATION: EudraCT 2016-001436-35. FUNDING: F.R.S.-FNRS Belgium, Wallonie-Bruxelles International, ULiège, Fondation Simone et Pierre Clerdent, European Regional Development Fund

Two analogy strategies: The cases of mind metaphors and introspection

Analogical reasoning is often employed in problem-solving and metaphor interpretation. This paper submits that, as a default, analogical reasoning addressing these different tasks employs different mapping strategies: In problem-solving, it employs analogy-maximising strategies (like structure mapping, Gentner & Markman 1997); in metaphor interpretation, analogy-minimising strategies (like ATT-Meta, Barnden 2015). The two strategies interact in analogical reasoning with conceptual metaphors. This interaction leads to predictable fallacies. The paper supports these hypotheses through case-studies on ‘mind’-metaphors from ordinary discourse, and abstract problem-solving in the philosophy of mind, respectively: It shows that (1) default metaphorical interpretations for vision- and space-cognition metaphors can be derived with a variant of the analogy-minimising ATT-Meta approach, (2) philosophically influential introspective conceptions of the mind can be derived with conceptual metaphors only through an analogy-maximising strategy, and (3) the interaction of these strategies leads to hitherto unrecognised fallacies in analogical reasoning with metaphors. This yields a debunking explanation of introspective conceptions

Treatment of systemic hypertension in insulin-treated diabetes mellitus with rilmenidine.

The effects of a new alpha 2 agonist (S 3341 or rilmenidine) on blood pressure (BP), glycemic control, lipid metabolism and renal function were investigated during a 16-week open study in 29 insulin-treated diabetic patients with mild to moderate hypertension. There were 17 men and 12 women aged 50.9 +/- 2.2 years (mean +/- standard error of the mean). Duration of diabetes and insulin therapy was 218 +/- 24 and 143 +/- 30 months. After 2 weeks of placebo, systolic and diastolic BP was 165 +/- 3 and 97 +/- 0.5 mm Hg, respectively (supine). Rilmenidine (S 3341) given alone at daily doses of 1 or 2 mg according to the clinical response led to a prompt and sustained decrease of systolic and diastolic BP (159 +/- 4 and 88 +/- 1 mm Hg after 2 weeks; 149 +/- 3 and 85 +/- 1 mm Hg after 12 weeks; p less than 0.01). Seventeen patients (59%) had normal BP (systolic BP less than 160; diastolic BP less than 90 mm Hg, supine) after 12 weeks of S 3341. Diuretics were associated with S 3341 for the nonresponders at week 12; this led to normalization of BP in 90% of the patients at the end of the study. Glycemic control was assessed by home glucose monitoring (5 determinations/1 day per week), 24-hour glucosuria and postprandial plasma glucose at the outpatient clinic (n = 7) as well as by the measurement of the glycosylated hemoglobin. None of these parameters was significantly affected by S 3341.(ABSTRACT TRUNCATED AT 250 WORDS

Treatment of hypertension in diabetic patients.

Hypertension, common in diabetic patients, worsens not only the risk of cardiovascular complications, but also that of microangiopathic complications (nephropathy, retinopathy) of diabetes mellitus. It is thus important to ensure the perfect control of even mild hypertension in diabetic patients. However, treatment sometimes becomes difficult given that certain categories of antihypertensive drugs interfere with blood glucose control and/or lipid metabolism, interfere with the symptomatology of hypoglycemia, or promote orthostatic hypotension, a complication of autonomic neuropathy. A study was undertaken to determine the effects of rilmenidine, administered for 16 weeks, in 29 diabetic patients treated with insulin and experiencing mild-to-moderate hypertension (supine diastolic blood pressure, 96.7 +/- 0.5 mmHg). Administered as single-drug therapy, rilmenidine rapidly normalized blood pressure (systolic blood pressure, less than 160 mmHg; diastolic blood pressure, no more than 90 mmHg--supine) in 17 patients; this persisted throughout the trial period. Addition of a diuretic after 12 weeks in the remaining 12 patients led to normalization of blood pressure in nine additional patients. Blood glucose control (evaluated at home by weekly blood glucose measurements and by glycosylated hemoglobin levels) was unaffected by treatment. Plasma levels of cholesterol (total, high-density lipoprotein and low-density lipoprotein), triglycerides and proteinuria (or microalbuminuria) showed no change during the course of the trial. In conclusion, rilmenidine offers an effective and safe treatment for mild-to-moderate hypertension in diabetic patients treated with insulin and does not interfere with their blood glucose control