Valeria Calsolaro

Neuroinflammation in Alzheimer's disease: Current evidence and future directions

Several attempts have been made to treat Alzheimers disease (AD) using anti‐amyloid strategies with disappointing results. It is clear that the “amyloid cascade hypothesis” alone cannot fully explain the neuronal damage in AD, as evidenced both by autopsy and imaging studies. Neuroinflammation plays a significant role in neurodegenerative diseases, whereas the debate is ongoing about its precise role, whether it is protective or harmful. In this review, we focus on the potential mechanism of glial activation and how local and systemic factors influence disease progression. We focus on neuroinflammation in AD, especially in the earliest stages, a vicious cycle of glial priming, release of pro‐inflammatory factors, and neuronal damage. We review the evidence from imaging studies, regarding the temporal relationship between amyloid deposition and neuroinflammation, the influence of systemic inflammation on glial activation, both in acute and chronic stimulation and the relevance of inflammation as a diagnostic and therapeutic target.

Neuroprotective effects of tetracyclines: molecular targets, animal models and human disease.

Tetracyclines are a class of antibiotics which could play a therapeutic role in several neurological disorders. Minocycline, extensively studied in animal models, decreased the size of ischaemic and haemorrhagic infarct. In Parkinsons disease models minocycline protected the nigrostriatal pathway, and in Huntingtons disease and motoneuron disease models delayed the progression of disease extending the lifespan. Finally, in human diseases such as stroke and multiple sclerosis tetracyclines seem to play some neuroprotective role. The main biological effects of tetracyclines are the inhibition of microglial activation, the attenuation of apoptosis, and the suppression of reactive oxygen species production. These mechanisms are involved in the pathogenesis of several neurodegenerative disorders. Several reports showed that minocycline reduced mitochondrial Ca(2+) uptake, stabilized mitochondrial membranes, and reduced the release into the cytoplasm of apoptotic factors. Other effects include up-regulation of mitochondrial bcl-2 (an antiapoptotic protein), direct scavenging of reactive oxygen species, and inhibition of mitogen activated protein kinases. It is still unclear which of these mechanisms plays the pivotal role in neuroprotective properties of tetracyclines. The anti-apoptotic effect of tetracyclines probably involves the mitochondrion. The major target for tetracyclines in neurodegeneration could lie within the complex network that links mitochondria, oxidative stress, poly (ADP-ribose) polymerase-1 and apoptosis. Here, we review the neuroprotective effects of tetracyclines in animal models and in human disease, and we focus on their possible mechanism(s) of action, with special regard to mitochondrial dysfunction in neurodegeneration.

Flutriciclamide (18F-GE180) PET: first in human PET study of novel 3rd generation in vivo marker of human translator protein

Neuroinflammation is associated with neurodegenerative disease. PET radioligands targeting the 18-kDa translocator protein (TSPO) have been used as in vivo markers of neuroinflammation, but there is an urgent need for novel probes with improved signal-to-noise ratio. Flutriciclamide (18F-GE180) is a recently developed third-generation TSPO ligand. In this first study, we evaluated the optimum scan duration and kinetic modeling strategies for 18F-GE180 PET in (older) healthy controls. Methods: Ten healthy controls, 6 TSPO high-affinity binders, and 4 mixed-affinity binders were recruited. All subjects underwent detailed neuropsychologic tests, MRI, and a 210-min 18F-GE180 dynamic PET/CT scan using metabolite-corrected arterial plasma input function. We evaluated 5 different kinetic models: irreversible and reversible 2-tissue-compartment models, a reversible 1-tissue model, and 2 models with an extra irreversible vascular compartment. The minimal scan duration was established using 210-min scan data. The feasibility of generating parametric maps was also investigated using graphical analysis. Results: 18F-GE180 concentration was higher in plasma than in whole blood during the entire scan duration. The volume of distribution (VT) was 0.17 in high-affinity binders and 0.12 in mixed-affinity binders using the kinetic model. The model that best represented brain 18F-GE180 kinetics across regions was the reversible 2-tissue-compartment model (2TCM4k), and 90 min resulted as the optimum scan length required to obtain stable estimates. Logan graphical analysis with arterial input function gave a VT highly consistent with VT in the kinetic model, which could be used for voxelwise analysis. Conclusion: We report for the first time, to our knowledge, the kinetic properties of the novel third-generation TSPO PET ligand 18F-GE180 in humans: 2TCM4k is the optimal method to quantify the brain uptake, 90 min is the optimal scan length, and the Logan approach could be used to generate parametric maps. Although these control subjects have shown relatively low VT, the methodology presented here forms the basis for quantification for future PET studies using 18F-GE180 in different pathologies.

Novel GLP-1 (Glucagon-Like Peptide-1) Analogues and Insulin in the Treatment for Alzheimer's Disease and Other Neurodegenerative Diseases.

AbstractThe link between diabetes mellitus and Alzheimer’s disease (AD) has been known for the last few decades. Since insulin and insulin receptors are known to be present in the brain, the downstream signalling as well as the effect of hyperinsulinemia have been extensively studied in both AD and Parkinson’s disease. Glucagon-like peptide-1 (GLP-1) is a hormone belonging to the incretin family, and its receptors (GLP-1Rs) can be found in pancreatic cells and in vascular endothelium. Interestingly, GLP-1Rs are found in the neuronal cell body and dendrites in the central nervous system (CNS), in particular in the hypothalamus, hippocampus, cerebral cortex and olfactory bulb. Several studies have shown the importance of both insulin and GLP-1 signalling on cognitive function, and many preclinical studies have been performed to evaluate the potential protective role of GLP-1 on the brain. Here we review the underlying mechanism of insulin and GLP-1 signalling in the CNS, as well as the preclinical data for the use of GLP-1 analogues such as liraglutide, exenatide and lixisenatide in neurodegenerative diseases.

Is there a primary role of the mitochondrial genome in Alzheimer's disease?

The “mitochondrial cascade hypothesis” could explain many of the biochemical, genetic and pathological features of sporadic Alzheimer’s disease (AD). Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress and accumulation of amyloid β, which in a vicious cycle reinforces mtDNA damage and oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, and despite the cognitive impairment frequently reported in patients with mtDNA mutation, no causative mutation in the mtDNA have been linked to AD. Indeed, results of studies on the role of mtDNA polymorphisms or haplogroups in AD are controversial. In this minireview, we summarize the actual knowledge about the involvement of mtDNA in AD pathology.

Cardiovascular Risk and Quality of Life in Elderly People with Mild Thyroid Hormone Deficiency

Subclinical hypothyroidism (sHT) is a common condition in the general population, the prevalence increases with age, especially in women. An association between sHT and increased coronary heart disease (CHD) and heart failure (HF) risk and mortality has been described. However, this association is far to be established in older people (>65 years), especially in the oldest old (>85 years). Individuals with sHT may experience symptoms that resemble those observed in the overt form of the disease, leading to an impaired quality of life (QoL). Although very old people are frequently frail and potentially more susceptible to the effects of a disease, few studies were designed to assess the effect of sHT on QoL in this subset of population. Interestingly, the serum TSH concentration curve of general population has a skewed distribution with a “tail” toward higher values, which is amplified with aging. Thus, the diagnosis of sHT and the interpretation of its potential effects on CV function and QoL in older people may be a challenge for the clinician. Giving these premises, we reviewed the English scientific literature available on National Library of Medicine (www.pubmed.com) since 1980 regarding hypothyroidism, sHT, elderly, cardiovascular risk, CHD or HF events and mortality, health-related QoL, and LT4 therapy. Consistent results among large prospective cohort studies suggest an age-independent relationship between sHT and HF progression, while an impact of sHT on CHD events and mortality is essentially reported in young adults (aged below 65–70 years) with long-lasting disease. Scanty data are available on QoL of older people with sHT (>65 years) and, generally, no significant alterations are described.

Nerve and muscle involvement in mitochondrial disorders: an electrophysiological study.

Involvement of the peripheral nervous system in mitochondrial disorders (MD) has been previously reported. However, the exact prevalence of peripheral neuropathy and/or myopathy in MD is still unclear. In order to evaluate the prevalence of neuropathy and myopathy in MD, we performed sensory and motor nerve conduction studies (NCS) and concentric needle electromyography (EMG) in 44 unselected MD patients. NCS were abnormal in 36.4% of cases, and were consistent with a sensori-motor axonal multineuropathy (multifocal neuropathy), mainly affecting the lower limbs. EMG evidence of myopathy was present in 54.5% of patients, again mainly affecting the lower limbs. Nerve and muscle involvement was frequently subclinical. Peripheral nerve and muscle involvement is common in MD patients. Our study supports the variability of the clinical expression of MD. Further studies are needed to better understand the molecular basis underlying the phenotypic variability among MD patients.

Cognitive Function and Quality of Life in Mild Thyroid Hormone Deficiency

Subclinical hypothyroidism (sHT) is very common in general population, especially in women and older people. sHT individuals may experience symptoms that resemble those observed in overt hypothyroidism, resulting in impaired quality of life (QOL). Asymptomatic patients may suffer a reduction in perceived health status due to the awareness of disease. Cognitive function represents one of the most important domains of the QOL questionnaires. Given the intrinsic relationship between cognitive status and QOL it is worth to address these topics together, in a systematic review of the literature. Thus, we reviewed the English scientific literature available on National Library of Medicine (www.pubmed.com) sine 1980 regarding hypothyroidism, sHT, elderly, L-thyroxine (LT4) therapy, QOL, cognition, brain. We supplemented the search with records from personal files, textbooks, and relevant articles. The possible link, at molecular level, between cognition and thyroid failure was also assessed. Conflicting results on the association between sHT and cognitive and health related QOL impairment are still present, although the most recent, naturalistic studies did not find any significant relationship. Interestingly, a reduction in health related QOL is frequently reported in patients with thyroid autoimmune diseases regardless of thyroid dysfunction. We also report most significant patents on the topic.

Tetracycline treatment in patients with progressive external ophthalmoplegia

Mancuso M, Orsucci D, Calsolaro V, LoGerfo A, Allegrini L, Petrozzi L, Simoncini C, Rocchi A, Trivella F, Murri L, Siciliano G.
Tetracycline treatment in patients with progressive external ophthalmoplegia.
Acta Neurol Scand: 2011: 124: 417–423.
© 2011 John Wiley & Sons A/S.

Degree of Peripheral Thyroxin Deiodination, Frailty, and Long-Term Survival in Hospitalized Older Patients

Context Although the association between low free triiodothyronine (FT3) and poor outcome has been extensively reported in literature, the degree of peripheral thyroxin deiodination and its relationship with frailty and survival in hospitalized older patients has not yet been fully established. The aim of the current study was to evaluate the possible correlation between FT3/free thyroxine (FT4) ratio reduction, an indirect marker of thyroxin deiodination impairment, and frailty status and survival in hospitalized older patients. Methods We consecutively enrolled older patients, hospitalized in the geriatrics ward of the University of Pisa. At admission, Multidimensional Geriatric Assessment (MGA) and Multi Prognostic Index (MPI), an indirect measure of frailty, were obtained from all the patients. Causes of hospitalization and prevalence of delirium were recorded. Blood samples for FT3, FT4, and thyrotropin value evaluation were drawn after an overnight fast. Results A total of 643 patients (83.8 ± 7.4 years, 53% women) were studied. FT3 was inversely and strongly correlated, whereas FT4 was moderately positively correlated with MGA parameters, MPI score (P < 0.001 and P < 0.05, respectively), and survival (P < 0.001 and P = 0.09, respectively). FT3/FT4 ratio reduction was highly associated with worse MGA (P < 0.001) and MPI scores (P < 0.0001), even in patients without low FT3. The inclusion of FT3 in the final model of multivariate Cox regression confirmed the independent role of FT3/FT4 ratio in predicting survival (P = 0.005). Conclusion Overall, our study documented a strong association between FT3/FT4 ratio reduction, a surrogate marker of peripheral thyroxin deiodination, and frailty. Moreover, FT3/FT4 ratio value emerged as independent marker of survival, even in patients with normal FT3 values.