Cortical plasticity is correlated with cognitive improvement in Alzheimer’s disease patients after rTMS treatment

ObjectiveRepetitive transcranial magnetic stimulation (rTMS) has been widely used in non-invasive treatments for different neurological disorders. Few biomarkers are available for treatment response prediction. This study aims to analyze the correlation between changes in long-term potentiation (LTP)-like cortical plasticity and cognitive function in patients with Alzheimer’s disease (AD) that underwent rTMS treatment.MethodsA total of 75 AD patients were randomized into either 20 Hz rTMS treatment at the dorsolateral prefrontal cortex (DLPFC) group (n = 37) or a sham treatment group (n = 38) for 30 sessions over six weeks (five days per week) with a three-month follow-up. Neuropsychological assessments were conducted using the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment-Cognitive Component (ADAS-Cog). The cortical plasticity reflected by the motor-evoked potential (MEP) before and after high-frequency repetitive TMS to the primary motor cortex (M1) was also examined prior to and after the treatment period.ResultsThe results showed that the cognitive ability of patients who underwent the MMSE and ADAS-Cog assessments showed small but significant improvement after six weeks of rTMS treatment compared with the sham group. The cortical plasticity improvement correlated to the observed cognition change.ConclusionsCortical LTP-like plasticity could predict the treatment responses of cognitive improvements in AD patients receiving rTMS intervention. This warrants future clinical trials using cortical LTP as a predictive marker.     

Taste in mild cognitive impairment and Alzheimer’s disease

In this prospective study we investigated the quantitative and qualitative taste function of patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). 29 healthy, elderly subjects, 29 MCI and 30 AD patients were tested using a validated taste test, the “taste strips”. Additionally, odor identification, odor discrimination, odor threshold, the mini-mental state examination (MMSE) and Apo E epsilon 4 status were examined. Regarding taste, there was a significant reduction of total taste scores and also the score for individual tastes on either side of the tongue between controls and MCI/AD patients. There was no significant difference in the taste scores between MCI and AD patients. A taste test may be a useful procedure for differentiating between healthy subjects and patients with MCI/AD in a clinical context. For diagnosing MCI versus AD, further tests such as smell test, MMSE, Apo E epsilon 4 status, FDG-PET and MRI appear to be useful.     

Cognitive training in Alzheimer’s disease: a controlled randomized study

This controlled randomized single-blind study evaluated the effects of cognitive training (CT), compared to active music therapy (AMT) and neuroeducation (NE), on initiative in patients with mild to moderate Alzheimer’s disease (AD). Secondarily, we explored the effects of CT on episodic memory, mood, and social relationships. Thirty-nine AD patients were randomly assigned to CT, AMT, or NE. Each treatment lasted 3 months. Before, at the end, and 3 months after treatment, neuropsychological tests and self-rated scales assessed initiative, episodic memory, depression, anxiety, and social relationships. At the end of the CT, initiative significantly improved, whereas, at the end of AMT and NE, it was unchanged. Episodic memory showed no changes at the end of CT or AMT and a worsening after NE. The rates of the patients with clinically significant improvement of initiative were greater after CT (about 62%) than after AMT (about 8%) or NE (none). At the 3-month follow-up, initiative and episodic memory declined in all patients. Mood and social relationships improved in the three groups, with greater changes after AMT or NE. In patients with mild to moderate AD, CT can improve initiative and stabilize memory, while the non-cognitive treatments can ameliorate the psychosocial aspects. The combining of CT and non-cognitive treatments may have useful clinical implications.     

Insulin resistance: an emerging link in Alzheimer’s disease

Relentless progression of Alzheimer’s disease (AD) poses a grave situation for the biomedical community to tackle. Agents starting as hot favorites in clinical trials have failed in later stages and it is time we reconsidered our approaches to intervene the disease. Quite some interesting work in the last decade has introduced a new school of thought which factors in neuronal glycemic imbalance as a major component for the development of AD. Insulin resistance in the brain has brought forward subsequent sequelae which might work towards amyloid accretion and/or tau hyperphosphorylation. It is also pointed out that insulin works by distributing iron to neuronal tissue and an insulin resistant state throws it off gear leading to iron overloading of neurons which is ultimately detrimental. A relatively recent investigation finds the role of c-Jun-N-terminal kinase (JNK3) in AD which also seems to bear a link with insulin resistance.     

Abnormal spatial and non-spatial cueing effects in mild cognitive impairment and Alzheimer’s disease

Our aim was to further characterize the clinical concept of mild cognitive impairment (MCI). We examined visual attention-related processing in 12 patients with amnestic MCI, 16 healthy older adults and 16 patients with Alzheimer’s disease (AD) by measuring performance on computer-based tests of attentional disengagement, alerting ability, and inhibition of return. Unlike the healthy older controls, the patients with AD and the patients with amnestic MCI exhibited a significant detriment in both the ability to disengage attention from an incorrectly cued location and the ability to use a visual cue to produce an alerting effect. The pattern of results displayed by the MCI group indicates that patients who only appear clinically to suffer from a deficit in memory also display a deficit in specific aspects of visual attention-related processing, which closely resemble the magnitude seen in AD.     

Retinal alterations in mild cognitive impairment and Alzheimer’s disease: an optical coherence tomography study

Retinal nerve fiber layer thickness (RNFL) measured by means of Optical Coherence Tomography (OCT) has been used as a marker not only of ophthalmologic diseases but also of neurodegenerative diseases such as Alzheimer’s disease (AD) and mild cognitive impairment (MCI). The purpose of this work was to demonstrate that patients with amnestic MCI show an intermediate RNFL thickness between normality and AD, and a macular volume and thickness as well. In a cross-sectional study we consecutively recruited 18 patients with AD, 21 with MCI, and 41 healthy controls. OCT was performed in all of them to measure circumpapillary RNFL thickness in µm, as well as macular volume and thickness. In the analysis of variance we saw that RNFL was thinner in MCI patients compared with controls, and it was also thinner in AD patients compared with MCI patients and controls. With regard to the macular measurements in mm³, MCI patients had the greatest macular volume in comparison with AD patients and controls. In turn the controls had greater macular volume than AD patients. The decreased RNFL thickness in MCI and AD patients suggests loss of retinal neurons and their axons. The increased thickness and macular volume have never been reported before in aMCI. This finding could be explained by inflammation and/or gliosis in early stages of AD. OCT could be a useful marker of AD for early detection and monitoring progression.     

Cardiac autonomic modulation and cognitive status in Alzheimer’s disease

Introduction  

Although nervous structures affected in Alzheimer’s disease are also implicated in autonomic nervous system function, the relationship between autonomic and cognitive functions was not still investigated.     

Progress in Alzheimer’s disease

After more than one century from Alois Alzheimer and Gaetano Perusini’s first report, progress has been made in understanding the pathogenic steps of Alzheimer’s disease (AD), as well as in its early diagnosis. This review discusses recent findings leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological markers. In addition, treatment options will be discussed, with emphasis on new disease-modifying compounds and future trial design suitable to test these drugs in an early phase of the disease.     

Astrocytes in Alzheimer’s disease

The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs.     

Treatments in Alzheimer’s disease

Journal of Neurology -     

Somatic comorbidities and Alzheimer’s disease treatment

Therapeutic strategies in Alzheimer’s disease (AD) must take into account the characteristics of elderly people, who often have somatic comorbidities. Moreover, demented patients are more frequently frailer than older people. They have a higher number of admissions to hospital, a greater prevalence of complications and an increased risk of death. Therapeutic decisions for these patients have to be approached cautiously: aging, a more elevated comorbidity/polytherapy index and frailty contribute to enhance the risk of pharmacological adverse events and drug interactions. The aim of the present study was to focus on risk–benefit profile of pharmacological therapy for AD in relation to somatic comorbidities that often affect these patients. A Medline search (from 2001 to 2012) was performed using as key words dementia, Alzheimer’s disease, drug treatment, somatic comorbidities, side effects/adverse events and elderly. Cholinesterase inhibitors (ChEIs) and memantine represent the main pharmacological strategies effective in reducing the progression of cognitive decline and functional loss in AD. Many conditions very common in the elderly may restrict the use of ChEIs and/or treatment efficacy in AD patients. Memantine has a good efficacy and tolerability profile with better safety in pulmonary, cardiovascular and central nervous system comorbidities compared to ChEIs. Drug interactions with memantine are also more favorable since they concern mostly drugs not commonly used in the elderly. Only a careful evaluation of the associated somatic diseases, taking into account different drugs safety indexes and tolerability, can lead to personalized treatment management, in order to maximize drug efficacy and optimize quality of life.     

The role of event-related potentials in cognitive decline in Alzheimer’s disease

ObjectivesEarly diagnosis and monitoring of disease progression have become vital in clinical practice as disease modifying treatments for Alzheimer’s disease (AD) become available. This one-year prospective study aimed to clarify the usefulness of event-related potentials (ERPs) in cognitive decline and elucidate their cognitive significance in AD.MethodsUsing the Cognitive Abilities Screening Instrument (CASI) and ERPs, probable AD patients, mild cognitive impairment (MCI) patients, and normal controls were recruited.ResultsThe AD and MCI patients had significantly decreased cognitive function and manifested a delay of P300 latency. The P300 latencies demonstrated significantly more prolongation than their baseline values in probable AD and MCI patients, although their CASI scores showed no statistically significant decline. Whereas N100, P200, and N200 components did not reach statistical differences between groups either in the baseline or follow-up assessments and did not show significant change on follow-up.ConclusionThe combination of neuropsychological tests and P300 measurements proved useful in improving reliability and increasing sensitivity to early cognitive decline or disease progression in AD patients.SignificanceThe P300 latency may reflect cognitive decline more sensitively than neuropsychological tests in the longitudinal follow-up of AD patients.     

Abnormal visual search in mild cognitive impairment and Alzheimer’s disease

Our aim was to further characterize the clinical concept of mild cognitive impairment (MCI). We examined the status of visual attention-related processing in such patients in relation to healthy older adults and patients with Alzheimer’s disease (AD) by measuring performance on a computer-based visual search task. We tested 20 older adult control participants, 13 patients with amnestic mild cognitive impairment and 12 patients with AD. Patients with AD and with MCI exhibited a significant detriment in visual search performance compared to the older adult controls. The deficit in visual search was greater for the patients with AD than the patients with MCI. The pattern of results displayed by the MCI group indicates that patients who appear clinically to suffer only from a deficit in memory also display a deficit in visual attention-related processing, which although not as severe as those with AD, represents a significant detriment in such performance compared to that seen in healthy ageing.     

Plasma lipids metabolism in mild cognitive impairment and Alzheimer’s disease

Objectives: Expression of phospholipids and related molecules could provide panels of multiple biomarkers searching for the signature of Alzheimer’s disease (AD). The aim of the present study was to quantify ten phospholipids and simultaneously determine phospholipase A₂ (PLA₂) activity in blood of mild cognitive impairment (MCI) and AD patients.

Methods: Thirty-four AD, 20?MCI and 25 controls were enrolled. The phospholipids where analysed using the AbsoluteIDQ^® p180 Kit. PLA₂ activities were accessed in platelets by a radio-enzymatic assay.

Results: The study failed to fix the ten phospholipids as a panel to predict AD; the levels of PCaaC36:6, PCaaC40:6 and C16:1-OH were lower in MCI than in controls (P?=?0.041, P?=?0.012, P?=?0.044 respectively). PCaaC40:2 levels were lower in MCI than in AD (P?=?0.041). The converters MCI-AD showed at baseline lower levels of PCaaC40:2 (P?=?0.050) and PCaaC40:6 (P?=?0.037) than controls. iPLA₂ activity was reduced in AD and MCI than in controls (P?2 (r?=?0.680; P?=?0.001) and sPLA₂ (r?=?0.601; P?=?0.004); PCaaC40:1 and iPLA₂ (r?=?0.503; P?=?0.020); PCaaC40:6 and tPLA₂ (r?=?0.532; P?=?0.013) and sPLA₂ (r?=?0.523; P?=?0.015).

Conclusions: Lipids metabolites in plasma might indirectly indicate changes in neuronal membrane and this deregulation can outline the transition between healthy and diseased brains.     

Magnetic resonance imaging in Alzheimer’s disease and mild cognitive impairment

Journal of Neurology - Research utilizing magnetic resonance imaging (MRI) has been crucial to the understanding of the neuropathological mechanisms behind and clinical identification of...     

“Keep up the good work!”: A case study of the effects of a specific cognitive training in Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative condition characterized by significant impairment in multiple cognitive domains. In recent years, the development of cognitive trainings in AD has received significant attention. In the present case study we designed a cognitive training program (GEO, Geographical Exercises for cognitive Optimization) based on an errorless paradigm and tailored to the patient’s cultural interests. The aim of this training was to investigate the potential for acquiring and possibly retaining both procedural and verbal knowledge in early-stage AD. This study involved an 80-year-old female patient diagnosed with early-stage AD, and 10 matched healthy subjects. Participants were asked to perform the two GEO training tasks: a “puzzle-like” task for procedural memory, and an “association” task for verbal memory. Both the patient and the healthy controls were subsequently trained with GEO using the same two tasks for 2 months. Although the patient’s performance before training in both tasks was poor compared to healthy controls, after the training these differences disappeared. Our results showed that the patient was able to acquire new procedural abilities and verbal knowledge, and that her achievements were stable at the follow-up testing scheduled 3 months after the end of the intervention. This case study suggests a potentially useful strategy for cognitive training in AD.     

Current concepts in therapeutic strategies targeting cognitive decline and disease modification in Alzheimer’s disease

Alzheimer’s disease is a progressive neurodegenerative disorder and the leading cause of dementia in the Western world. Postmortem, it is characterized neuropathologically by the presence of amyloid plaques, neurofibrillary tangles, and a profound gray matter loss. Neurofibrillary tangles are composed of an abnormally hyperphosphorylated intracellular protein called tau, tightly wound into paired helical filaments and thought to impact microtubule assembly and protein trafficking, resulting in the eventual demise of neuronal viability. The extracellular amyloid plaque deposits are composed of a proteinacious core of insoluble aggregated amyloid-β (Aβ) peptide and have led to the foundation of the amyloid hypothesis. This hypothesis postulates that Aβ is one of the principal causative factors of neuronal death in the brains of Alzheimer’s patients. With multiple drugs now moving through clinical development for the treatment of Alzheimer’s disease, we will review current and future treatment strategies aimed at improving both the cognitive deficits associated with the disease, as well as more novel approaches that may potentially slow or halt the deadly neurodegenerative progression of the disease.