Transcranial magnetic stimulation (TMS)/repetitive TMS in mild cognitive impairment and Alzheimer's disease

Several Transcranial Magnetic Stimulation (TMS) techniques can be applied to noninvasively measure cortical excitability and brain plasticity in humans. TMS has been used to assess neuroplastic changes in Alzheimer's disease (AD), corroborating findings that cortical physiology is altered in AD due to the underlying neurodegenerative process. In fact, many TMS studies have provided physiological evidence of abnormalities in cortical excitability, connectivity, and plasticity in patients with AD. Moreover, the combination of TMS with other neurophysiological techniques, such as high‐density electroencephalography (EEG), makes it possible to study local and network cortical plasticity directly. Interestingly, several TMS studies revealed abnormalities in patients with early AD and even with mild cognitive impairment (MCI), thus enabling early identification of subjects in whom the cholinergic degeneration has occurred. Furthermore, TMS can influence brain function if delivered repetitively; repetitive TMS (rTMS) is capable of modulating cortical excitability and inducing long‐lasting neuroplastic changes. Preliminary findings have suggested that rTMS can enhance performances on several cognitive functions impaired in AD and MCI. However, further well‐controlled studies with appropriate methodology in larger patient cohorts are needed to replicate and extend the initial findings. The purpose of this paper was to provide an updated and comprehensive systematic review of the studies that have employed TMS/rTMS in patients with MCI and AD.     

Characterizing mild cognitive impairment in Parkinson's disease

There is growing interest in identifying Parkinson's disease (PD) patients with mild cognitive impairment (PD‐MCI), but widely disparate criteria have been used. We assessed 143 PD patients and 50 matched controls on 20 measures across 4 cognitive domains (executive function, attention and working memory, learning and memory, visuoperception). Twenty‐four patients met criteria for dementia (PD‐D); nondementia patients were classified as either with normal cognition or MCI for 12 neuropsychological criteria. We compared the influence of these criteria on the distribution of global cognitive performance in the resulting PD‐MCI groups relative to the control and PD‐D groups. Different criteria produced substantial variation in the proportion of PD‐MCI cases identified. Fourteen percent PD‐MCI was found when using 2 scores in 1 domain at 2 standard deviations (SD) below normative scores, with no controls identified as MCI, through to 89% PD‐MCI with 1 score in 1 domain at 1 SD below normative scores, when 70% of controls were identified as MCI. The balance of cases with impaired cognition but not those with generally intact cognition was better served by using criteria that required 2 specific deficit scores or deficits across 2 domains. As comparisons with external normative data may have greater applicability across centers, we suggest that 2 scores at ?1.5 SD within any single domain (30% PD‐MCI) or 1 score at ?1.5 SD in each of 2 domains (37% PD‐MCI) provide suitable criteria to minimize the inclusion of cognitively well patients. Clinical dementia rating did not improve the relative identification of cognitively impaired and unimpaired nondementia PD patients. © 2011 Movement Disorder Society     

Defining mild cognitive impairment in Parkinson's disease

Our purpose was to characterize a state of mild cognitive impairment (MCI) in Parkinson's disease (PD) (PD‐MCI) that would be analogous to the MCI that is posited as a precursor of Alzheimer's disease (AD). We categorized 86 PD subjects in a brain bank population as either cognitively normal (PD‐CogNL), PD‐MCI using criteria that included a 1.5 standard deviation or greater deficit upon neuropsychological testing consistently across at least one cognitive domain without dementia, and PD dementia (PD‐D) using DSM‐IV criteria. Twenty‐one percent of our PD sample met criteria for PD‐MCI, 62% were PD‐CogNL, and 17% had PD‐D. The mean duration of PD and MMSE scores of the PD‐MCI group were intermediate and significantly different from both PD‐CogNL and PD‐D. The cognitive domain most frequently abnormal in PD‐MCI was frontal/executive dysfunction followed by amnestic deficit. Single domain PD‐MCI was more common than PD‐MCI involving multiple domains. We conclude that a stage of clinical cognitive impairment in PD exists between PD‐CogNL and PD‐D, and it may be defined by applying criteria similar to the MCI that is posited as a precursor of AD. Defining PD‐MCI offers an opportunity for further study of cognitive impairment in PD and targets for earlier therapeutic intervention. © 2007 Movement Disorder Society     

Evaluation of mild cognitive impairment subtypes in Parkinson's disease

Mild cognitive impairment in Parkinson's disease (PD‐MCI) is common and increases the risk for dementia. Establishing distinct PD‐MCI cognitive subtypes could be valuable for eventually predicting those most likely to convert to dementia. However, the study of PD‐MCI subtypes has not yielded consistent results among cohorts. To determine whether there are distinct cognitive subtypes among participants diagnosed with PD‐MCI in the Pacific Northwest Udall Center Clinical Consortium, we cognitively subtyped 95 patients with PD‐MCI, using the Movement Disorders Society Task Force diagnostic guidelines. Psychometric test scores were then subjected to principle components factor analysis to determine whether similar cognitive subgroups could be identified using statistical methodology. Multiple‐domain PD‐MCI was diagnosed in 95% of the sample, and a range of cognitive impairments were noted. Factor analysis yielded seven factors and demonstrated overlap of phonemic verbal fluency on two factors, as well as the loading of verbal fluency on the same factor as a visuospatial measure; however, these factors did not partition the sample into distinct cognitive subtypes. Separation of cognitive subtypes based on the current PD‐MCI criteria, or via statistical methods, may not provide sufficient information to describe distinct PD groups. Future efforts to validate the PD‐MCI criteria and identify combinations of genetic or other risk factors for cognitive impairment are warranted. © 2014 International Parkinson and Movement Disorder Society     

Measuring mild cognitive impairment in patients with Parkinson's disease

We examined the frequency of Parkinson disease with mild cognitive impairment (PD‐MCI) and its subtypes and the accuracy of 3 cognitive scales for detecting PD‐MCI using the new criteria for PD‐MCI proposed by the Movement Disorders Society. Nondemented patients with Parkinson's disease completed a clinical visit with the 3 screening tests followed 1 to 3 weeks later by neuropsychological testing. Of 139 patients, 46 met Level 2 Task Force criteria for PD‐MCI when impaired performance was based on comparisons with normative scores. Forty‐two patients (93%) had multi‐domain MCI. At the lowest cutoff levels that provided at least 80% sensitivity, specificity was 44% for the Montreal Cognitive Assessment and 33% for the Scales for Outcomes in Parkinson's Disease‐Cognition. The Mini‐Mental State Examination could not achieve 80% sensitivity at any cutoff score. At the highest cutoff levels that provided specificity of at least 80%, sensitivities were low (≤44%) for all tests. When decline from estimated premorbid levels was considered evidence of cognitive impairment, 110 of 139 patients were classified with PD‐MCI, and 103 (94%) had multi‐domain MCI. We observed dramatic differences in the proportion of patients who had PD‐MCI using the new Level 2 criteria, depending on whether or not decline from premorbid level of intellectual function was considered. Recommendations for methods of operationalizing decline from premorbid levels constitute an unmet need. Among the 3 screening tests examined, none of the instruments provided good combined sensitivity and specificity for PD‐MCI. Other tests recommended by the Task Force Level 1 criteria may represent better choices, and these should be the subject of future research. © 2013 Movement Disorder Society     

metabolic profiling of Parkinson's disease and mild cognitive impairment

Background : Early diagnosis of Parkinson's disease and mild cognitive impairment is important to enable prompt treatment and improve patient welfare, yet no standard diagnostic test is available. Metabolomics is a powerful tool used to elucidate disease mechanisms and identify potential biomarkers. Objectives : The objective of this study was to use metabolic profiling to understand the pathoetiology of Parkinson's disease and to identify potential disease biomarkers. Methods : This study compared the serological metabolomic profiles of early‐stage Parkinson's patients (diagnosed < 12 months) to asymptomatic matched controls using an established array based detection system (DiscoveryHD4?, Metabolon, UK), correlating metabolite levels to clinical measurements of cognitive impairment. Results : A total of 1434 serological metabolites were assessed in early‐stage Parkinson's disease cases (n = 41) and asymptomatic matched controls (n = 40). Post–quality control, statistical analysis identified n = 20 metabolites, predominantly metabolites of the fatty acid oxidation pathway, associated with Parkinson's disease and mild cognitive impairment. Receiver operator curve assessment confirmed that the nine fatty acid oxidation metabolites had good predictive accuracy (area under curve = 0.857) for early‐stage Parkinson's disease and mild cognitive impairment (area under curve = 0.759). Conclusions : Our study indicates that fatty acid oxidation may be an important component in the pathophysiology of Parkinson's disease and may have potential as a diagnostic biomarker for disease onset and mild cognitive impairment. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Biomarkers for dementia and mild cognitive impairment in Parkinson's disease

Cognitive decline is one of the most frequent and disabling nonmotor features of Parkinson's disease. Around 30% of patients with Parkinson's disease experience mild cognitive impairment, a well‐established risk factor for the development of dementia. However, mild cognitive impairment in patients with Parkinson's disease is a heterogeneous entity that involves different types and extents of cognitive deficits. Because it is not currently known which type of mild cognitive impairment confers a higher risk of progression to dementia, it would be useful to define biomarkers that could identify these patients to better study disease progression and possible interventions. In this sense, the identification among patients with Parkinson's disease and mild cognitive impairment of biomarkers associated with dementia would allow the early detection of this process. This review summarizes studies from the past 25 years that have assessed the potential biomarkers of dementia and mild cognitive impairment in Parkinson's disease patients. Despite the potential importance, no biomarker has as yet been validated. However, features such as low levels of epidermal and insulin‐like growth factors or uric acid in plasma/serum and of Aß in CSF, reduction of cerebral cholinergic innervation and metabolism measured by PET mainly in posterior areas, and hippocampal atrophy in MRI might be indicative of distinct deficits with a distinct risk of dementia in subgroups of patients. Longitudinal studies combining the existing techniques and new approaches are needed to identify patients at higher risk of dementia. © 2016 International Parkinson and Movement Disorder Society     

Clinical differences among mild cognitive impairment subtypes in Parkinson's disease

Mild cognitive impairment is increasingly recognized as a construct in Parkinson's disease (PD) and occurs in about 25% of nondemented PD patients. Although executive dysfunction is the most frequent type of cognitive deficit in PD, the cognitive phenotype of PD mild cognitive impairment (PD-MCI) is broad. PD-MCI subtypes are represented by amnestic and nonamnestic domain impairment as well as single- and multiple-domain impairment. However, it is unclear whether patients with different PD-MCI subtypes also differ in other clinical characteristics in addition to cognitive profile. We studied 128 PD-MCI subjects at our Movement Disorders center, comparing clinical, motor, and behavioral characteristics across the PD-MCI subtypes. We found varying proportions of impairment subtypes: nonamnestic single domain, 47.7%; amnestic multiple domain, 24.2%; amnestic single domain, 18.8%; and nonamnestic multiple domain, 9.5%. Attentional/executive functioning and visuospatial abilities were the most frequently impaired domains. PD-MCI subtypes differed in their motor features, with nonamnestic multiple-domain PD-MCI subjects showing particularly pronounced problems with postural instability and gait. Differences among PD-MCI subtypes in age, PD duration, medication use, mood or behavioral disturbances, and vascular disease were not significant. Thus, in addition to differing cognitive profiles, PD-MCI subtypes differed in motor phenotype and severity but not in mood, behavioral, or vascular comorbidities. Greater postural instability and gait disturbances in the nonamnestic multiple-domain subtype emphasize shared nondopaminergic neural substrates of gait and cognition in PD. Furthermore, increased burden of cognitive dysfunction, rather than type of cognitive deficit, may be associated with greater motor impairment in PD-MCI. ? 2012 Movement Disorder Society.     

Cortical thinning associated with mild cognitive impairment in Parkinson's disease

The aim of this study was to investigate patterns of cortical atrophy associated with mild cognitive impairment in a large sample of nondemented Parkinson's disease (PD) patients, and its relation with specific neuropsychological deficits. Magnetic resonance imaging (MRI) and neuropsychological assessment were performed in a sample of 90 nondemented PD patients and 32 healthy controls. All underwent a neuropsychological battery including tests that assess different cognitive domains: attention and working memory, executive functions, memory, language, and visuoperceptual‐visuospatial functions. Patients were classified according to their cognitive status as PD patients without mild cognitive impairment (MCI; n = 43) and PD patients with MCI (n = 47). Freesurfer software was used to obtain maps of cortical thickness for group comparisons and correlation with neuropsychological performance. Patients with MCI showed regional cortical thinning in parietotemporal regions, increased global atrophy (global cortical thinning, total gray matter volume reduction, and ventricular enlargement), as well as significant cognitive impairment in memory, executive, and visuospatial and visuoperceptual domains. Correlation analyses showed that all neuropsychological tests were associated with cortical thinning in parietotemporal regions and to a lesser extent in frontal regions. These results provide neuroanatomic support to the concept of MCI classified according to Movement Disorders Society criteria. The posterior pattern of atrophy in temporoparietal regions could be a structural neuroimaging marker of cognitive impairment in nondemented PD patients. All of the neuropsychological tests reflected regional brain atrophy, but no specific patterns were seen corresponding to impairment in distinct cognitive domains. © 2014 International Parkinson and Movement Disorder Society     

Ventricular enlargement and mild cognitive impairment in early Parkinson's disease

Mild cognitive impairment (MCI) may predict future development of dementia in Parkinson's disease (PD). We aimed to examine the extent of subcortical brain atrophy in patients with early PD with and without MCI compared to normal controls (NC). Participating in a population‐based study were 43 early, drug‐naïve PD patients and 41 NC. Eleven patients were classified with MCI (MCI PD) and 32 patients without (non‐MCI PD). Volumetric segmentation of 3D‐T1 weighted brain MRI was performed using FreeSurfer. Groups were compared applying MANCOVA corrected for total intracranial volume, age, and sex. Results showed that left inferior lateral ventricle and third ventricle volumes were significantly larger in MCI PD than in non‐MCI PD and NC. Fourth ventricular size in MCI PD was significantly different from NC and highly correlated with memory performance in MCI PD patients. This suggests that cognitive dysfunction in early PD may be associated with ventricular enlargement. © 2010 Movement Disorder Society     

Bilateral subthalamic nucleus stimulation does not improve prolonged P300 latencies in Parkinson's disease

Bilateral deep brain stimulation is an effective treatment for most motor signs of Parkinson's disease (PD), but the effects on cognitive functions are less clear. We therefore examined the effects of bilateral deep brain stimulation on central information processing, using the event-related auditory P300 potential as an electrophysiological index of mental chronometry. Eight PD patients with bilateral stimulators within the subthalamic nuclei (STN) and eight age-matched controls participated. Patients were examined after overnight withdrawal of antiparkinson medication, both “on” and “off” stimulation (in random sequence). The P300 and reaction times were recorded using an auditory oddball paradigm. P300 latencies were prolonged in PD patients off stimulation (440 ± 45 ms) compared to controls (397 ± 16 ms; P < 0.05). STN stimulation significantly reduced clinical disease severity (as indexed by the Unified Parkinson's Disease Rating Scale) and markedly improved reaction times, but did not improve the prolonged P300 latencies in PD patients (429 ± 36 ms). These results confirm that P300 latencies are prolonged in PD. Significantly, bilateral STN stimulation did not improve this electrophysiological measure of cognitive impairment, even though motor disability was markedly reduced. This suggests that some dopa-responsive features are resistant to STN stimulation, possibly due to involvement of dopaminergic deficits outside the nigrostriatal pathway, which are not influenced by outflow from the STN. Received: 24 August 2000, Received in revised form: 30 October 2000, Accepted: 3 November 2000     

Transcranial magnetic stimulation in cognitive rehabilitation

Repetitive transcranial magnetic stimulation (rTMS) can generate an increase or a decrease of neuronal excitability, which can modulate cognition and behaviour. Transcranial magnetic stimulation-induced cortical changes have been shown to result in neural plasticity. Thus, TMS provides an important opportunity to gain more insight into the mechanisms responsible for the remarkable flexibility of the central nervous system. The aim of this review was to cover the topics that could be useful when using TMS in the cognitive rehabilitation field after brain damage. The basic TMS principles are introduced, together with the clinical application for diagnosis and prognosis, the biological aspects, and the use in cognitive neuroscience studies. Finally, several hypotheses are discussed to explain the likely mechanisms induced by TMS that favour the recovery of a function after brain damage and cause the adult brain to undergo plasticity. The possibility of non-invasively interacting with the functioning of the brain and its plasticity mechanisms - a possibility that may eventually lead to cognitive and behavioural modifications - opens new and exciting scenarios in the cognitive neurorehabilitation field.     

Anosognosia in very mild Alzheimer's disease but not in mild cognitive impairment

OBJECTIVE: To study awareness of cognitive dysfunction in patients with very mild Alzheimer's disease (AD) and subjects with mild cognitive impairment (MCI). METHODS: A complaint interview covering 13 cognitive domains was administered to 82 AD and 79 MCI patients and their caregivers. The patient groups were comparable according to age and education, and Mini Mental State Examination (MMSE) scores were > or =24 in all cases. The discrepancy between the patients' and caregivers' estimations of impairments was taken as a measure of anosognosia. RESULTS: Self-reports of cognitive difficulties were comparable for AD and MCI patients. However, while in comparison to caregivers MCI patients reported significantly more cognitive impairment (p < 0.05), AD patients complained significantly less cognitive dysfunctions (p < 0.001). CONCLUSIONS: While most MCI patients tend to overestimate cognitive deficits when compared to their caregiver's assessment, AD patients in early stages of disease underestimate cognitive dysfunctions. Anosognosia can thus be regarded as a characteristic symptom at a stage of very mild AD (MMSE > or =24) but not MCI. Accordingly, medical history even in mildly affected patients should always include information from both patient and caregiver.     

Transcranial magnetic stimulation over dorsolateral prefrontal cortex in Parkinson's disease.

OBJECTIVE: Several studies have shown that repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) is effective in the treatment of depression in patients with Parkinson disease (PD). However, since research into the effect of this type of rTMS regime on motor function is limited, we studied the effect of rTMS over the DLPFC on the motor functions in PD patients. METHODS: Thirteen patients were randomly assigned into 2 groups, one receiving real-rTMS (90% of resting motor threshold, 10 Hz, 450 pulses-day for 10 consecutive days) over the DLPFC contralateral to the more affected side, and the other group receiving sham-rTMS. Assessment included a clinical motor evaluation using part III of the Unified Parkinson's Disease Rating Scale (UPDRS), and several motor tasks. The UPDRS was applied before and after 10 days of rTMS. Finger tapping, reach movement, grip movement and gait were measured in each session before and after the rTMS over the 10 day period. RESULTS: Statistical analysis (ANOVA for repeated measures; group *day *side *rTMS) only showed a significant effect for finger tapping, reach movement and gait for the factor day. No significant change was reported for the UPDRS in any group. CONCLUSIONS: Application of rTMS over the DLPFC as a 10 day course had no significant effect on motor functions and clinical motor status, and the improvement in performance of motor tasks can be attributed to the effects of practice. SIGNIFICANCE: rTMS over the DLPFC did not lead to any motor improvement in PD patients.     

帕金森病患者轻度认知损害的临床调查

目的 研究帕金森病(Parkinson's disease,PD)伴有轻度认知功能缺损(mild cognitiveimpairment,MCI,即PD-MCI)患者患病率及其神经心理学特征.方法 设立PD患者组(n=103)及健康对照组(n=32)进行比较.心理学测验工具由MMSE、痴呆评定量表及其他神经心理学测试组成,汉密尔顿抑郁量表用以评定患者的抑郁程度.结果 (1)21例(20.4%)PD患者被诊断为痴呆,37例(35.9%)患者认知功能完整,45例(43.7%)患者有MCI;(2)与认知正常的PD患者相比,PD-MCI患者年龄更大,PD起病更晚,且运动损害更为严重;(3)PD-MCI的患病率和神经心理学特征与PD症状主要累及何侧及分型有一定关系:左侧组比右侧组患者出现MCI的概率要高(74.2%和42.2%,χ2=7.589,P<0.05);震颤为主型患者与混合型患者相比,Stroop测词试验(SWT)的耗时(s)显著减少(80.8±39.9和94.4±30.0,t=3.332,P<0.01).结论在PD患者中,筛查出PD-MCI患者有着重要的临床意义,有助于临床医生针对性地处理不同PD患者,并易化对其预后的判断.