Prefrontal Cortex Activity and Gait in Parkinson's Disease With Cholinergic and Dopaminergic Therapy

Degradation of striatal dopamine in Parkinson's disease (PD) may initially be supplemented by increased cognitive control mediated by cholinergic mechanisms. Shift to cognitive control of walking can be quantified by prefrontal cortex activation. Levodopa improves certain aspects of gait and worsens others, and cholinergic augmentation influence on gait and prefrontal cortex activity remains unclear. This study examined dopaminergic and cholinergic influence on gait and prefrontal cortex activity while walking in PD. A single-site, randomized, double-blind crossover trial examined effects of levodopa and donepezil in PD. Twenty PD participants were randomized, and 19 completed the trial. Participants were randomized to either levodopa + donepezil (5 mg) or levodopa + placebo treatments, with 2 weeks with treatment and a 2-week washout. The primary outcome was change in prefrontal cortex activity while walking, and secondary outcomes were change in gait and dual-task performance and attention. Levodopa decreased prefrontal cortex activity compared with off medication (effect size, −0.51), whereas the addition of donepezil reversed this decrease. Gait speed and stride length under single- and dual-task conditions improved with combined donepezil and levodopa compared with off medication (effect size, 1 for gait speed and 0.75 for stride length). Dual-task reaction time was quicker with levodopa compared with off medication (effect size, −0.87), and accuracy improved with combined donepezil and levodopa (effect size, 0.47). Cholinergic therapy, specifically donepezil 5 mg/day for 2 weeks, can alter prefrontal cortex activity when walking and improve secondary cognitive task accuracy and gait in PD. Further studies will investigate whether higher prefrontal cortex activity while walking is associated with gait changes. © 2020 International Parkinson and Movement Disorder Society     

Visual feedback has differential effects on reaching movements in Parkinson’s and Alzheimer’s disease

We examine the role of visual feedback in the programming and execution of reaching movement in patients with Parkinson’s disease without cognitive impairment and patients with Alzheimer’s disease without extrapyramidal signs. Controls were normally aging subjects. All subjects moved a cursor to targets on a digitizing tablet without seeing their limb. Starting and target positions were always visible on a screen while, during movement, cursor position was either visible or blanked. They were instructed to make uncorrected movements, as fast and as accurate as possible without minimizing reaction time. In absence of visual feedback, movement accuracy in patients with AD was severely impaired. Hand paths of parkinsonian patients were as accurate as normal subjects’ with similar temporal velocity profiles and movement speed. With cursor feedback, accuracy was the same in the three groups, although movement speed and transport phase in patients with Alzheimer’s disease were significantly reduced compared to the other groups. Also, movements of parkinsonian patients showed shorter transport phase and lower mean velocity than controls’. The different characteristics of the motor performance suggests that in the two diseases visual information is used differently for both motor programming and execution: patients with Alzheimer’s disease, while scarcely using feed forward commands, relied on continuous on-line external cues. The correlation of motor performance with cognitive impairment argues against the hypothesis of basal ganglia involvement in AD. The motor abnormalities we found may represent early subclinical manifestation of apraxic disturbance. Parkinsonian patients showed higher reliance on feedback commands only with cursor feedback: this could be explained by their difficulty in engaging effectively automatic routines when distractors are present.     

Inflammation in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disorder to date. Next to its classical histopathological characteristics such as deposition of fibrillogenic amyloid β peptides and neurofibrillary tangles, an inflammatory component of the disease has been identified. This article will review which cell types contribute to this phenomenon and which pro- and anti-inflammatory mediators are being released in the AD brain. Further, it will be discussed whether there are any known pathogenetic factors that may facilitate the induction and persistence of neuroinflammatory mechanisms. While neuroinflammation has mostly been quoted as a reaction to neurodegenerative events, more recent evidence suggests that it can feedback stimulate on neurodegenerative pathomechanisms including the generation of amyloid β peptides, thereby establishing a vicious and self-perpetuating cycle. Along this line, pro- and anti-inflammatory mechanisms may also contribute to the chronicity and duration of the disease. Therefore, anti-inflammatory treatment strategies should be evaluated as possible future therapeutics for AD.     

Topography of callosal atrophy reflects distribution of regional cerebral volume reduction in Alzheimer’s disease

It has been suggested that regional corpus callosum atrophy in Alzheimer’s disease (AD) may serve as an in vivo index of neuronal loss in the neocortex. In this study total and regional size of the corpus callosum was evaluated with respect to the volumes of the frontal, temporal, and parietal lobes in 38 patients with AD (NINCDS-ADRDA criteria) using quantitative magnetic resonance imaging. Twenty healthy subjects matched for age and gender served as a control group. All quantitative measurements were performed by manual tracing using personal computer-based software. Both total size and as the five measured regional subsections were significantly smaller in AD when compared to the control subjects. The severity of dementia was significantly correlated with the size of the middle sections of the corpus callosum (rostral body and midbody). Within the AD group, the rostral body of the corpus callosum was significantly correlated with the frontal lobe volumes, the midbody was correlated with the temporal lobe volumes, and size of the splenium was correlated with the parietal lobe volumes. We conclude that callosal atrophy in AD reflects the severity and pattern of cortical neuronal damage. Correlations between regional callosal atrophy and severity of dementia indicate that interhemispheric cortico-cortical disconnection may contribute to the dementia syndrome.     

Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease

Mateo I, Infante J, Sánchez‐Juan P, García‐Gorostiaga I, Rodríguez‐Rodríguez E, Vázquez‐Higuera JL, Berciano J, Combarros O. Serum heme oxygenase‐1 levels are increased in Parkinson’s disease but not in Alzheimer’s disease.
Acta Neurol Scand: 2010: 121: 136–138.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – Oxidative stress is implicated in Parkinson’s disease (PD) and Alzheimer’s disease (AD), and heme oxygenase‐1 (HO‐1) is a potent antioxidant overexpressed in PD substantia nigra and AD cerebral cortex and hippocampus, indicating a possible up‐regulation of antioxidant defenses in both neurodegenerative diseases. The role of HO‐1 in peripheral blood of PD and AD patients remains unresolved. Methods – We measured serum HO‐1 levels in 107 patients with PD, 105 patients with AD, 104 controls for PD and 120 controls for AD. Results – The median serum concentration of HO‐1 was significantly higher in PD patients (2.04 ng/ml) compared with that of PD controls (1.69 ng/ml, P = 0.016), with PD patients predominating over controls in the upper tertile of serum HO‐1 levels, whereas there was more PD controls than PD patients in the lower tertile (P = 0.006). Median serum levels of HO‐1 did not differ significantly between AD patients and AD controls. Conclusion – The increase of serum HO‐1 levels in PD patients could indicate a systemic antioxidant reaction related to a chronic oxidative stress state in PD brain.     

Metabotropic Glutamate Receptor 2 and 3 Gene Expression in The Human Prefrontal Cortex and Mesencephalon in Schizophrenia

Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are implicated in schizophrenia. We characterized mGluR2 and 3 mRNA in the human prefrontal cortex (PFC) and mesencephalon, and then compared cases with schizophrenia to matched controls. In the human brain, both receptors were expressed in the PFC and, unlike the rodent, in dopaminergic (DA) cell groups. In schizophrenia, we found significantly higher levels of mGluR2 mRNA in the PFC white matter. The expression of mGluR2, 3 in DA cells provide a mechanism for glutamate to modulate dopamine release in the human brain and this species-specific difference may be critical to understanding rodent models in schizophrenia.     

Altered expression of the synuclein family mRNA in Lewy body and Alzheimer’s disease

The main objective of this study was to determine if levels of α-, β- and/or γ-synuclein mRNAs are differentially affected in brains of Lewy body disease (LBD) and Alzheimer’s disease (AD) patients, compared to controls. In control cases, highest levels of expression were observed in the neocortex and the lowest in basal ganglia and substantia nigra. β-Synuclein was the most abundant message (75–80%), followed by γ-synuclein (10–15%) and α-synuclein (8–10%). Analysis of the superior temporal cortex, a region selectively affected in LBD and AD, showed that compared to controls, levels of α-synuclein were increased in cases of diffuse LBD (DLBD), levels of β-synuclein were decreased in AD and DLBD, and levels of γ-synuclein were increased in AD cases. This study suggests that a critical balance among products of the synuclein gene is important to maintain normal brain function and that alterations in this balance might be associated with neurodegenerative disorders.     

Gesture comprehension,knowledge and production in Alzheimer’s disease

Background and purpose: Although apraxia is a typical consequence of Alzheimer’s disease (AD), the profile of apraxic impairments is still subject to debate. Here, we analysed apraxia components in patients with AD with mild‐to‐moderate or moderately severe dementia. Methods: Thirty‐one patients were included. We first evaluated simple gestures, that is, the imitation of finger and hand configurations, symbolic gestures (recognition, production on verbal command and imitation), pantomimes (recognition, production on verbal command, imitation and production with the object), general knowledge and complex gestures (tool–object association, function–tool association, production of complex actions and knowledge about action sequences). Tests for dementia (Mini Mental State Examination and the Dementia Rating Scale), language disorders, visual agnosia and executive function were also administered. Results: Compared with controls, patients showed significant difficulties (P ≤ 0.01) in subtests relating to simple gestures (except for the recognition and imitation of symbolic gestures). General knowledge about tools, objects and action sequences was less severely impaired. Performance was frequently correlated with the severity of dementia. Multiple‐case analyses revealed that (i) the frequency of apraxia depended on the definition used, (ii) ideomotor apraxia was more frequent than ideational apraxia, (iii) conceptual difficulties were slightly more frequent than production difficulties in the early stage of AD and (iv) difficulties in gesture recognition were frequent (especially for pantomimes). Conclusion: Patients with AD can clearly show gesture apraxia from the mild–moderate stage of dementia onwards. Recognition and imitation disorders are relatively frequent (especially for pantomimes). We did not find conceptual difficulties to be the main problem in early‐stage AD.     

Cyanobacterial neurotoxin BMAA in ALS and Alzheimer’s disease

Objective – The aim of this study was to screen for and quantify the neurotoxic amino acid β‐N‐methylamino‐l ‐alanine (BMAA) in a cohort of autopsy specimens taken from Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and non‐neurological controls. BMAA is produced by cyanobacteria found in a variety of freshwater, marine, and terrestrial habitats. The possibility of geographically broad human exposure to BMAA had been suggested by the discovery of BMAA in brain tissues of Chamorro patients with ALS/Parkinsonism dementia complex from Guam and more recently in AD patients from North America. These observations warranted an independent study of possible BMAA exposures outside of the Guam ecosystem. Methods – Postmortem brain specimens were taken from neuropathologically confirmed cases of 13 ALS, 12 AD, 8 HD patients, and 12 age‐matched non‐neurological controls. BMAA was quantified using a validated fluorescent HPLC method previously used to detect BMAA in patients from Guam. Tandem mass spectrometric (MS) analysis was carried out to confirm the identification of BMAA in neurological specimens. Results – We detected and quantified BMAA in neuroproteins from postmortem brain tissue of patients from the United States who died with sporadic AD and ALS but not HD. Incidental detections observed in two out of the 24 regions were analyzed from the controls. The concentrations of BMAA were below what had been reported previously in Chamarro ALS/ Parkinsonism dementia complex patients, but demonstrated a twofold range across disease and regional brain area comparisons. The presence of BMAA in these patients was confirmed by triple quadrupole liquid chromatography/mass spectrometry/mass spectrometry. Conclusions – The occurrence of BMAA in North American ALS and AD patients suggests the possibility of a gene/environment interaction, with BMAA triggering neurodegeneration in vulnerable individuals.     

Computerized cognition assessment during acetylcholinesterase inhibitor treatment in Alzheimer’s disease

Wesnes K, Edgar C, Andreasen N, Annas P, Basun H, Lannfelt L, Zetterberg H, Blennow K, Minthon L. Computerized cognition assessment during acetylcholinesterase inhibitor treatment in Alzheimer’s disease.
Acta Neurol Scand: 2010: 122: 270–277.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – Alzheimer’s disease assessment scale‐cognitive subscale (ADAS‐Cog) has become a standard clinical trials outcome for cognition, but has been recognized as deficient in areas including coverage of cognitive domains, sensitivity and standardization. Computerized test batteries may address some of these issues. The cognitive drug research computerized assessment (CDR) system is validated in Alzheimer’s disease (AD). This study was designed to further evaluate validity in relation to ADAS‐Cog, mini mental state examination (MMSE) and cerebrospinal fluid (CSF) biomarkers and psychometric properties, in a population of Alzheimer’s patients on stable anticholinesterase treatment. Materials and methods – Patients completed cognition assessments, CSF and blood sampling at baseline and 6 months later. Data for 65 patients were evaluated. Results – The CDR system demonstrated good psychometric properties in this population. Measures of psychomotor speed showed possible sensitivity to decline over 6 months. Conclusions – There are a number of methodological problems with current cognition assessment methodology for clinical trials. Computerized measures and in particular millisecond reaction time measures, may address many of these issues.     

Altered frontostriatal coupling in pre‐manifest Huntington’s disease: effects of increasing cognitive load

Background and purpose: Functional neuroimaging studies have suggested a dysfunction of prefrontal regions in clinically pre‐symptomatic individuals with the Huntington’s disease (HD) gene mutation (pre‐HD) during cognitive processing. The objective of this study was to test the impact of cognitive demand on prefrontal connectivity in pre‐HD individuals. Methods: Sixteen healthy controls and sixteen pre‐HD subjects were studied using functional MRI and a verbal working memory task with increasing cognitive load. Load‐dependent functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) was investigated by means of psychophysiological interactions. Results: In pre‐HD subjects, aberrant functional connectivity of the left DLPFC was found at high working memory load levels only. Compared with healthy controls, pre‐HD individuals exhibited lower connectivity strength in the left putamen, the right anterior cingulate and the left medial prefrontal cortex. Pre‐HD individuals close to the onset of motor symptoms additionally exhibited lower connectivity strength in the right putamen and the left superior frontal cortex. The connectivity strength in the left putamen was associated with several clinical measures including CAG repeat length, Unified Huntington's Disease Rating Scale motor score and predicted years to manifest symptom onset. Conclusion: These findings suggest that early prefrontal connectivity abnormalities in pre‐HD individuals are modulated by cognitive demand.     

Hippocampal estrogen β-receptor immunoreactivity is increased in Alzheimer’s disease

Post-menopausal estrogen use reduces the risk and severity of Alzheimer’s disease (AD). The present study investigates the distribution of both estrogen receptors ERα and ERβ in the human hippocampus in aged controls and in AD cases with immunohistochemistry. No ERα immunoreactivity was observed both in controls and in AD cases. On the other hand, ERβ was observed in some neuronal cells in the hippocampal subfields CA1–4, in astrocytes and in extracellular deposits both in controls and AD cases. The ERβ immunoreactivity was distinctly increased in all AD cases in cellular and extracellular localizations indicating a role for ERβ-mediated estrogen effects in AD-related neuropathology. This study provides the first demonstration of ERβ in human hippocampus in aged controls compared to AD cases.     

Wnt signaling function in Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disease with progressive dementia accompanied by three main structural changes in the brain: diffuse loss of neurons; intracellular protein deposits termed neurofibrillary tangles (NFT) and extracellular protein deposits termed amyloid or senile plaques, surrounded by dystrophic neurites. Two major hypotheses have been proposed in order to explain the molecular hallmarks of the disease: The ‘amyloid cascade’ hypothesis and the ‘neuronal cytoskeletal degeneration’ hypothesis. While the former is supported by genetic studies of the early-onset familial forms of AD (FAD), the latter revolves around the observation in vivo that cytoskeletal changes – including the abnormal phosphorylation state of the microtubule associated protein tau – may precede the deposition of senile plaques. Recent studies have suggested that the trafficking process of membrane associated proteins is modulated by the FAD-linked presenilin (PS) proteins, and that amyloid β-peptide deposition may be initiated intracellularly, through the secretory pathway. Current hypotheses concerning presenilin function are based upon its cellular localization and its putative interaction as macromolecular complexes with the cell-adhesion/signaling β-catenin molecule and the glycogen synthase kinase 3β (GSK-3β) enzyme. Developmental studies have shown that PS proteins function as components in the Notch signal transduction cascade and that β-catenin and GSK-3β are transducers of the Wnt signaling pathway. Both pathways are thought to have an important role in brain development, and they have been connected through Dishevelled (Dvl) protein, a known transducer of the Wnt pathway. In addition to a review of the current state of research on the subject, we present a cell signaling model in which a sustained loss of function of Wnt signaling components would trigger a series of misrecognition events, determining the onset and development of AD.     

Memory with emotional content,brain amygdala and Alzheimer’s disease

Objectives – A highly adaptive aspect of human memory is the enhancement of explicit, consciously accessible memory by emotional stimuli. We studied the performance of Alzheimer’s disease (AD) patients and elderly controls using a memory battery with emotional content, and we correlated these results with the amygdala and hippocampus volume. Methods – Twenty controls and 20 early AD patients were subjected to the International Affective Picture System (IAPS) and to magnetic resonance imaging‐based volumetric measurements of the medial temporal lobe structures. Results – The results show that excluding control group subjects with 5 or more years of schooling, both groups showed improvement with pleasant or unpleasant figures for the IAPS in an immediate free recall test. Likewise, in a delayed free recall test, both the controls and the AD group showed improvement for pleasant pictures, when education factor was not controlled. The AD group showed improvement in the immediate and delayed free recall test proportional to the medial temporal lobe structures, with no significant clinical correlation between affective valence and amygdala volume. Conclusion – AD patients can correctly identify emotions, at least at this early stage, but this does not improve their memory performance.     

Zinc takes the center stage: its paradoxical role in Alzheimer’s disease

There is compelling evidence that the etiology of Alzheimer’s disease (AD) involves characteristic amyloid-β (Aβ) deposition, oxidative stress, and anomalous metal–Aβ protein interaction. New studies have implicated redox active metals such as copper, iron, and zinc as key mediating factors in the pathophysiology of Alzheimer’s disease. There is also evidence that drugs with metal chelating properties could produce a significant reversal of amyloid-β plaque deposition in vitro and in vivo. This paper reviews current observations on the etiologic role of zinc in AD. We also discuss the interactions of zinc and copper with Aβ, a factor that purportedly facilitates disease processes. Finally, we review the protective role of zinc against Aβ cytotoxicity and hypothesize how the apparent effect of zinc on AD pathology may be paradoxical, The Zinc Paradox. Indeed, complex pathologic stressors inherent to the Alzheimer’s diseased brain dictate whether or not zinc will be neuroprotective or neurodegenerative. Further research on the zinc paradox in AD is needed in order to elucidate the exact role zinc plays in AD pathogenesis.