Most patients with Parkinson's disease have cognitive and behavior disorders during the course of their illness.In this study we consider practical aspects of the treatment of patients with Parkinson's disease who have such problems.Better understanding of both normal and abnormal physiology of the basal ganglia and their connections makes it possible to suggest hypotheses regarding the cause of these disorders. The combination of lesions of multiple subcorticocortical systems with different degrees of direct cortical pathology due to Lewy bodies and neuritic plaques may explain most of the changes, from depression to dementia.It is necessary to test these concepts using studies based on specific predictions derived from pathophysiological models. Until this is done, the clinical treatment of cognitive and compartmental disorders in Parkinson's disease will continue to be symptomatic, complex and controversial.
Cortical hyperexcitability has been demonstrated in Alzheimer's disease (AD) across basic science and clinical research. Amyloid-beta (Aβ) accumulation in AD causes synaptic dysfunction and disruption of cortical networks, including cortical hyperexcitability with epileptiform discharges. Clinically, seizures are seen in 8-16% of AD patients. However, there is currently no established, objective tool that can quantify hyperexcitability in vivo. Transcranial magnetic stimulation with electromyography (TMS-EMG) can measure cortical excitability, and may be a useful, noninvasive metric of hyperexcitability in AD. TMS-EMG measures of cortical excitability were assessed in left motor cortex in 37 healthy cognitive agers (HCA) (aged 50-87, 17 female) and 41 participants with early AD (aged 52-86, 22 female). Early AD participants were either diagnosed with mild AD by a board-certified neurologist, or mild cognitive impairment with evidence of Aβ deposition on [18F]Florbetapir PET. Resting motor threshold (RMT) was measured as the minimum stimulation intensity (% max. stimulator output; MSO) required to elicit a motor evoked potential (MEP) on at least 5/10 trials. Excitation-Inhibition (E-I balance) was assessed as the difference between paired-pulse TMS measures of intracortical facilitation (ICF) and short interval intracortical inhibition (SICI). In a subset of the dataset, MEP amplitudes were assessed over a range of stimulation intensities (30-100 %MSO) and fitted to a 3-parameter logistic function to yield Input-Output (IO) curves. Separate general linear models were used to test for group differences in RMT and E-I balance between early AD and HCA, while controlling for age and gender. RMT was not significantly different between groups. E-I balance was decreased in early AD compared to HCA (p=0.025). IO curve parameters did not show significant group differences in slope or inflection point, but did show a higher asymptote in the early AD group (p=0.01).
Many patients with Alzheimer disease (AD) eventually develop extrapyramidal motor signs, such as rigidity, postural changes, and bradykinesia (slowness
Advances in functional neuroimaging have improved early detection and differential diagnosis of dementia. Moreover, these methods may be useful for study of the underlying pathophysiology of dementia, and may ultimately guide development of new therapies for dementia. Previous studies in patients with severe DLB have identified decreased metabolism or blood flow in the occipital cortex relative to AD, and this pattern of decreased function has been proposed to be diagnostic for DLB. In this study, comparison of regional cerebral blood flow (rCBF) was made between subjects with mild diffuse Lewy body disease (DLB), age-matched controls, and subjects with mild Alzheimer's disease (AD). Diagnosis of AD or DLB was made by experienced clinicians using established clinical criteria. Eleven DLB, 20 AD, and 18 control subjects underwent arterial-spin labeled perfusion MRI (ASL-pMRI) and a neuropsychological test battery that included the Mini-mental State Examination, verbal fluency, and memory testing. MRI was performed on a 3 Tesla whole body scanner using the head coil. ASL was performed using flow driven adiabatic inversion and an improved version of a previously published method for subtracting off-resonance saturation effects. The blood flow images were spatially normalized and group comparisons performed using Statistical Parametric Mapping (SPM2). With a threshold of p< 0.0.5 uncorrected for multiple comparisons, significant differences in rCBF were found for both the DLB and AD groups in frontal and parieto-occipital cortex. However, the magnitude in reduction in blood flow was significantly more pronounced in the DLB group compared to the AD group, despite a milder degree of cognitive impairment amongst the subjects with DLB. The regional pattern of decreased rCBF measured with ASL may have limited specificity for separating mild DLB from mild AD. Clinically, patients with DLB have been observed to exhibit dramatic clinical response to treatment with cholinesterase inhibitors, and a more severe cholinergic deficit is known to be present in DLB relative to AD. The hypoperfusion in association areas detected by ASL-pMRI in DLB may therefore be associated with decreased cholinergic function.
It is well known that certain cognitive abilities decline with age. The ability to form certain new declarative memories, particularly memories for facts and events, has been widely shown to decline with advancing age. In contrast, the effects of aging on the ability to form new procedural memories such as skills are less well known, though it appears that older adults are able to acquire some new procedural skills over practice. The current study examines the effects of normal aging on procedural memory more closely by comparing the effects of aging on the encoding or acquisition stage of procedural learning versus its effects on the consolidation, or between-session stage of procedural learning. Twelve older and 14 young participants completed a sequence-learning task (the Serial Reaction Time Task) over a practice session and at a re-test session 24 hours later. Older participants actually demonstrated more sequence skill during acquisition than the young. However, older participants failed to show skill improvement at re-test as the young participants did. Age thus appears to have a differential effect upon procedural learning stages such that older adults' skill acquisition remains relatively intact, in some cases even superior, compared to that of young adults, while their skill consolidation may be poorer than that of young adults. Although the effect of normal aging on procedural consolidation remains unclear, aging may actually enhance skill acquisition on some procedural tasks.
Transcranial magnetic stimulation (TMS) is a neurophysiologic technique to noninvasively induce a controlled current pulse in a prespecified cortical target. This can be used to transiently disrupt the function of the targeted cortical region and explore causal relations to behavior, assess cortical reactivity, and map out functionally relevant brain regions, for example during presurgical assessments. Particularly when applied repetitively, TMS can modify cortical excitability and the effects can propagate trans-synaptically to interconnected cortical, subcortical, and spinal cord regions. As such, TMS can be used to assess the functional integrity of neural circuits and to modulate brain activity with potential therapeutic intent.
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