Cerebral and CSF amyloid load, and recovery of semantic material in Alzheimer disease patients

According to the new diagnostic criteria, the term “Alzheimer Disease” (AD) refers to a set of neuropathological changes that can be evaluated in vivo, rather than to a specific clinical symptomatology1. It is now widely accepted that β-Amyloid (Aβ42) in the cerebrospinal fluid is a valid indicator of alteration of the pathophysiological state, associated with fibrillar deposits of cerebral β-amyloid2. Comparative studies between imaging and autopsy findings have established that amyloid PET images are a valid in vivo surrogate for deposition of fibrillar β-amyloid3-10. We analyzed the values of cerebral spinal cord (CSF) biomarkers in 40 patients with clinical diagnosis of AD. Two groups emerged: the first with both clinical and liquor biomarkers consistent with AD; the second was clinically in line with AD, but it was missing its pathognomic CSF biomarkers. At this point we asked ourselves about the nosological entity of the second group. All patients underwent flutemetamol-PET and the second group was dichotomically divided into two more groups based on the PET report. Schematically: Group 1: CSF + / PET +; Group 2: CSF- / PET +; Group 3: CSF- / PET-. Our study then correlated the PET images through statistical software (spm12) in order to highlight any differences in cerebral β-amyloid accumulation. The first comparison was conducted between Group 1 and 2 revealing a significant accumulation of β-amyloid in the regions of the posterior cingulate gyrus. The posterior cingulate gyrus is involved in maintaining spatio-temporal orientation and memory functions, thanks to the connections with the parahippocampal cortex11. Involvement of the posterior cingulate gyrus is classic in patients with a typical clinical presentation of AD11. This result is also in agreement with the typical cerebral distribution of Aβ in AD (Braak and Braak stages)12 and highlights instead the possibility of non-typical deposits in the second group, for which a different etiopathogenetic mechanism from "ordinary” AD is hypothesized13. In support of this assumption, the results of the second comparison conducted between Group 2 versus Group 1, which showed a pattern of regional accumulation of cerebral β-amyloid in the regions of the frontal lobe, are explanatory. On the basis of this evidence, we hypothesized that the CSF- / PET + condition represents a clinical variant of the AD pathology defined in the literature as "frontal variant of the AD"13. Several studies have found that in the frontal variant of AD, the neuro-fibrillary tangle load (NFT) is about 10 times higher in the frontal cortex13 than in the typical AD group. On the other hand, patients with typical AD showed a greater accumulation of NFT in the entorhinal cortex, cingulate gyrus and temporal cortex13. Both evidences are consistent with the results of our study. Starting from the analysis of the neuropsychological tests carried out in AP patients behavioral and language alterations to the onset of illness have emerged, in addition to the memory impairment which is a pathognomonic sign of the typical AD. The typical AD refers to a pattern characterized by an early episodic memory loss followed by various combinations of deficits including attentional-executive deficit, language and visuospatial capacity deficits, which reflect the spread of the disease from the medial temporal lobe to other neocortical areas14-17. In contrast to this typical profile, the focal cortical variants of AD18 present an atypical symptomatological picture (executive dysfunctions19-20, deficits in design skills, behavioral abnormalities, impulsiveness, inattention to detail, inability to plan and language deficit21) . Despite the serious alterations to the tests that investigate the functioning of the frontal lobe, the performance of neuropsychological tests were similar to the typical AD group. This suggests that severe frontal deficiency is the main neuropsychological feature on top of an otherwise typical AD profile13. Several studies suggest that the deposition of fibrillar Aβ explains at most, a small part of the clinical-anatomical heterogeneity of AD13. In fact, in the frontal AD variant an increase in tangles of tau fibrils but not of amyloid plaques has been observed22-23. It is now widely accepted that in AD the neurofibrillary lesions begin to accumulate in the limbic and temporo-parietal regions and only then would they progress to the frontal and occipital cortex. Thus the frontal lobes would be affected by neurodegenerative lesions typical of AD in a subsequent temporal sequence12. It is therefore possible that in the AD variants there is a focal deficit that is indicative of a selective, early and prominent vulnerability of some regions of the brain that are normally involved in pato This result is also in agreement with the cerebral distribution typical of Aβ in AD (Braak and Braak stages)12 and highlights instead the possibility of non-typical deposits in the second group, for which a different etiopathogenetic mechanism is hypothesized from that "typical" of AD13. In support of this hypothesis, the results of the second comparison conducted between Group 2 versus Group 1, which showed a pattern of regional accumulation of cerebral β-amyloid in the regions of the frontal lobe (Fig.2), are explanatory. On the basis of this evidence, we hypothesized that the CSF-/PET + condition represents a clinical variant of the AD pathology defined in the literature as "frontal variant of the AD"13. Several studies have found that in the frontal variant of AD, the neuro-fibrillary tangle load (NFT) is about 10 times higher in the frontal cortex13 than in the typical AD group. On the other hand, patients with typical AD showed a greater accumulation of NFT in the entorhinal cortex, cingulate gyrus and temporal cortex13. Both evidences are consistent with the results of our study. Starting from the analysis of the neuropsychological tests carried out in AP patients, behavioral and language alterations to the onset of illness have emerged, in addition to the memory impairment which is a pathognomonic sign of the typical AD. Typical AD refers to a pattern characterized by an early episodic memory loss followed by various combinations of deficits including attentional-executive deficit, language and visuospatial capacity deficits, which reflect the spread of the disease from the medial temporal lobe to other neocortical areas14-17. In contrast to this typical profile, the focal cortical variants of AD18 present an atypical symptomatological picture (including executive dysfunctions19-20, deficits in planing skills, behavioral abnormalities, impulsiveness, inattention to detail, inability to plan and language deficit21) . Despite the serious alterations emerged at the tests investigating the functioning of the frontal lobe, the performance of neuropsychological tests were similar to the typical AD group. This suggests that severe frontal deficiency is the main neuropsychological feature on top of an otherwise typical AD profile13. Several studies suggest that the deposition of fibrillar Aβ explains at most a small part of the clinical-anatomical heterogeneity of AD13. Indeed, an increase in tau fibril tangles but not in amyloid plaques was observed in the frontal variant of AD.22-23. It is now widely accepted that in AD the neurofibrillary lesions begin to accumulate in the limbic and temporo-parietal regions and only afterwards they would progress towards the frontal and occipital cortex. Thus the frontal lobes would be affected by neurodegenerative lesions typical of AD in a subsequent temporal sequence12. It is therefore possible that in the AD variants there is a focal deficit that is indicative of a selective, early and prominent vulnerability of some brain regions which generally, as mentioned, will normally be involved in the AD pathology in a subsequent time sequence. This vulnerability would be caused by the primary deposition of tau at the frontal level24-28. On the other hand, the frontal variant of AD is characterized by a pathological process that does not seem to remain limited to the frontal lobes for a long time18. Aggregation of Aβ would be driven by the total flux of neuronal activity while tau aggregation would depend on trans-neuronal diffusion, generating neurodegeneration models that coincide with specific functional networks that eventually lead to specific clinical phenotypes (AD variants)13. A better understanding of the factors that drive the heterogeneity of these clinical phenotypes can provide important insights into the mechanisms of the disease and have direct implications on the diagnosis and management of patients with emerging disease-specific therapies18. Finally, in our study, the third and fourth comparisons were conducted between Group 1 and Group 3 and between Group 2 and Group 3 respectively. Both groups showed a significant pattern of accumulation of cerebral β-amyloid widespread almost in all brain areas. This result is not surprising, in light of the fact that Group 3 probably configures the SNAP Group (suspected non-Alzheimer's pathophysiology), or a syndrome defined by normal levels of amyloid biomarkers (CSF- / PET-) but neurodegeneration patterns evident at MRI or FDG-PET29 imaging study. In fact, from 10% to 30% of clinically diagnosed ADs do not show neuropathological alterations of AD during an autopsy30 and a similar proportion has Aβ31 or CSF Aβ42 levels normal31-40. Thus the multi-domain anamnestic phenotype of dementia is not specific. it may be the product of other diseases as well as AD31. To date, SNAP remains a not yet well-defined nosological entity. The clinical diagnosis of AD is often "incorrect" but there are significant differences with regard to clinical progress, genetic susceptibility and progression of the pathology, which have crucial implications for a precise and correct diagnosis, for clinical management and effectiveness of clinical trials on drugs29. SNAP is a very frequent condition in clinically normal subjects > 65 years and appears to be age-related. A study found that the frequency of SNAP was 0% in the age group between 50-60 years while it reached 24% around the age of 8929. However, the literature does not agree. The main controversy in the literature is whether SNAP is an indipendent pathological entity or can evolve into AD41. Some researchers believe that SNAP should be included as an integral part of the AD spectrum; if so, the pathogenetic explanation of the amyloid-centric models of AD and the concept of preclinical AD42 are wrong and should therefore be reviewed. On the contrary, if SNAP is a different entity from AD, the amyloid-centric models of AD and preclinical AD42 are completely consistent with current knowledge. In both cases, multiple studies have shown that the pathogenesis of SNAP is linked to the deposition of tau fibrils, which justify cerebral neurodegeneration; it would then be Aβ, even in small quantities, to act as the biological driver of taupathy, and cause the "spread" of tau in a widespread manner throughout the brain43,44. Therefore a better understanding of the factors that guide the clinical and etiopathogenetic heterogeneity of AD studied thanks to methods such as flutemetamol-PET can provide direct implications on correct diagnosis and prognostic precision in clinical practice. Furthermore, understanding the different nosological entities in study allows a better stratification of the patients in the future trials and the management of emerging specific therapies for this disease

How the cognitive reserve interacts with β-amyloid deposition in mitigating FDG metabolism: An observational study

This observational study had the aim to assess the interaction between cognitive reserve (CR) and cerebrospinal fluid β-amyloid1-42 (Aβ1-42) in modulating brain [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) metabolism in patients with moderate Alzheimer disease (AD).Twenty-seven patients with probable AD and 25 neurological normal subjects (NNS) entered the study. All participants had an FDG-PET scan, and AD patients also received a lumbar puncture to measure Aβ1-42, 181p-tau, and Tau concentrations. Based on years of formal education, AD patients were classified as highly educated-AD (years of formal education >5) or less educated-AD (years of formal education <5). By using a voxel-wise approach, we first investigated differences in the cerebral glucose uptake between AD and NNS, then we assessed the interaction between level of education (a proxy of CR) and cerebrospinal fluid biomarkers on FDG-PET metabolism in the patient groups.Significantly lower glucose uptake was observed in the posterior cingulate gyrus, in the precuneus, in the inferior and medial temporal gyrus, and in the inferior parietal lobule of AD patients compared with NNS. A significant interaction was found between CR and Aβ1-42 values on brain metabolism in the inferior and medial temporal gyrus bilaterally.The AD patients with higher CR level and marked signs of neuropathology showed glucose hypometabolism in regions typically targeted by AD pathology. This finding supports the hypothesis that CR partially compensates for the effect of Aβ plaques on cognitive impairment, helps in patients' clinical staging, and opens new possibilities for the development of nonpharmacological interventions

Bilateral putaminal necrosis and bronopol toxicity

Among alcohols, methanol intoxication is the most frequently associated with cerebral toxicity, causing retinal damage and putaminal necrosis. This consequence is believed to be due to the transformation of methanol into formic acid. We describe the case of a patient who presented with acute impairment of consciousness and tetraparesis after she had been drinking several bottles of a topical antiseptic solution (Lysoform Medical) containing 2-bromo-2-nitro-1,3-propandiol (bronopol) among excipients, in order to lose weight during previous months. Moreover, she had been on a strict slimming diet. Soon after admission, a severe respiratory and metabolic impairment became rapidly evident, requiring an intensive care unit admission. Cerebral MRI showed the presence of bilateral putaminal necrosis. She recovered in 10 days, surprisingly, without any evident clinical neurological signs. Methanol, also bronopol, when diluted in aqueous solution, at warm temperature and/or higher pH, may release formaldehyde, which is converted into formic acid, a basal ganglia toxic compound

Interaction between Cognitive Reserve and Biomarkers in Alzheimer Disease

Patients with comparable degree of neuropathology could show different cognitive impairments. This could be explained with the concept of cognitive reserve (CR), which includes a passive and an active component. In particular, CR is used to explain the gap between tissue damage and clinical symptoms that has been observed in dementia and, in particular, in patients affected by Alzheimer disease (AD). Different studies confirm brain neuroplasticity. Our preliminary study demonstrated that AD patients with high education showed a CR inversely associated with glucose uptake measured in fluorodeoxyglucose positron emission tomography (FDG-PET), whereas the inverse correlation was observed in AD patients with low education. In other words, our findings suggest that CR compensates the neurodegeneration and allows the maintenance of patients&rsquo; cognitive performance. Best understanding of the concept of CR could lead to interventions to slow cognitive aging or reduce the risk of dementia

Early recurrence of Tako-Tsubo cardiomyopathy in an elderly woman with amyotrophic lateral sclerosis: different triggers inducing different apical ballooning patterns

We report the case of early recurrence of Tako-Tsubo cardiomyopathy in an elderly woman with amyotrophic lateral sclerosis triggered by different stressors. A first episode with typical apical ballooning was anticipated by an emotional stress; a second, characterized by systolic anterior motion of the mitral valve associated with mitral regurgitation and severe intra-ventricular gradient, was precipitated by surgical stress and hypovolemia. We therefore hypothesize both a possible link between amyotrophic lateral sclerosis and Tako-Tsubo cardiomyopathy, and between different stressors and different Tako-Tsubo patterns

Intravenous lacosamide in seizure emergencies: Observations from a hospitalized in-patient adult population

Purpose to evaluate the efficacy and safety of intravenous (IV) lacosamide (LCM) in the treatment of seizure clusters (SC) and status epilepticus (SE) in hospitalized adult patients. Methods we prospectively analyzed treatment response, seizure outcome, and adverse effects of IV LCM in 38 patients with seizure emergencies (15 with SC, 23 with SE) during a hospital stay. The loading dose of IV LCM was 200–400 mg and the maintenance dose was 200–400 mg daily. Response to IV LCM was evaluated within 20 min, 4 h and 24 h of LCM infusion. Results an acute anti-seizure effect after IV LCM was especially evident when it was first used – (SC) or second line (established SE) treatment. In particular, 87% of SC patients (13/15) and 80% of established SE (8/10) demonstrated response to LCM treatment, while no patients with super-refractory SE (0/8) responded to IV LCM according to our criteria. The loading of IV LCM was well tolerated, with mild adverse effects (2/38 temporary dizziness). In most patients, during and after administration of the loading dose of IV LCM a temporary (30 min–1 h) sedation was observed. No ECG and laboratory values-changes were documented in any of the patients. Conclusions LCM is an effective and well-tolerated treatment when used to treat SC in hospitalized adult patients. As add-on therapy, it may be useful to stop seizure activity in patients with focal SE not responding to first/second-line intravenous AEDs

How the cognitive reserve interacts with ß-amyloid deposition in mitigating FDG metabolism: An observational study

This observational study had the aim to assess the interaction between cognitive reserve (CR) and cerebrospinal fluid ß-amyloid1-42 (Aß1-42) in modulating brain [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) metabolism in patients with moderate Alzheimer disease (AD).Twenty-seven patients with probable AD and 25 neurological normal subjects (NNS) entered the study. All participants had an FDG-PET scan, and AD patients also received a lumbar puncture to measure Aß1-42, 181p-tau, and Tau concentrations. Based on years of formal education, AD patients were classified as highly educated-AD (years of formal education >5) or less educated-AD (years of formal education <5). By using a voxel-wise approach, we first investigated differences in the cerebral glucose uptake between AD and NNS, then we assessed the interaction between level of education (a proxy of CR) and cerebrospinal fluid biomarkers on FDG-PET metabolism in the patient groups.Significantly lower glucose uptake was observed in the posterior cingulate gyrus, in the precuneus, in the inferior and medial temporal gyrus, and in the inferior parietal lobule of AD patients compared with NNS. A significant interaction was found between CR and Aß1-42 values on brain metabolism in the inferior and medial temporal gyrus bilaterally.The AD patients with higher CR level and marked signs of neuropathology showed glucose hypometabolism in regions typically targeted by AD pathology. This finding supports the hypothesis that CR partially compensates for the effect of Aß plaques on cognitive impairment, helps in patients' clinical staging, and opens new possibilities for the development of nonpharmacological interventions