Valeria Drago

Disease Tracking Markers for Alzheimer's Disease at the Prodromal (MCI) Stage

Older persons with Mild Cognitive Impairment (MCI) feature neurobiological Alzheimers Disease (AD) in 50% to 70% of the cases and develop dementia within the next 5 to 7 years. Current evidence suggests that biochemical, neuroimaging, electrophysiological, and neuropsychological markers can track the disease over time since the MCI stage (also called prodromal AD). The amount of evidence supporting their validity is of variable strength. We have reviewed the current literature and categorized evidence of validity into three classes: Class A, availability of multiple serial studies; Class B a single serial study or multiple cross sectional studies of patients with increasing disease severity from MCI to probable AD; and class C, multiple cross sectional studies of patients in the dementia stage, not including the MCI stage. Several Class A studies suggest that episodic memory and semantic fluency are the most reliable neuropsychological markers of progression. Hippocampal atrophy, ventricular volume and whole brain atrophy are structural MRI markers with class A evidence. Resting-state fMRI and connectivity, and diffusion MR markers in the medial temporal white matter (parahippocampus and posterior cingulum) and hippocampus are promising but require further validation. Change in amyloid load in MCI patients warrant further investigations, e.g. over longer period of time, to assess its value as marker of disease progression. Several spectral markers of resting state EEG rhythms that might reflect neurodegenerative processes in the prodromal stage of AD (EEG power density, functional coupling, spectral coherence, and synchronization) suffer from lack of appropriately designed studies. Although serial studies on late event-related potentials (ERPs) in healthy elders or MCI patients are inconclusive, others tracking disease progression and effects of cholinesterase inhibiting drugs in AD, and cross-sectional including MCI or predicting development of AD offer preliminary evidence of validity as a marker of disease progression from the MCI stage. CSF Markers, such as Aβ 1-42, t-tau and p-tau are valuable markers which support the clinical diagnosis of Alzheimers disease. However, these markers are not sensitive to disease progression and cannot be used to monitor the severity of Alzheimers disease. For Isoprostane F2 some evidence exists that its increase correlates with the progression and the severity of AD.

The slow-wave components of the cyclic alternating pattern (CAP) have a role in sleep-related learning processes.

Slow waves, a key feature of the EEG of NREM sleep, may be causally involved in producing a sleep-dependent, progressive downscaling of synaptic strength, which would lead to several benefits in terms of both cellular function and network performance. Also the A1 subtypes of the so-called cyclic alternating pattern (CAP) are composed mostly of slow waves and map over the frontal and prefrontal regions of the scalp. The aim of this study was to evaluate the eventual changes of CAP induced by an implicit learning paradigm which has already been shown to be able to increase locally sleep slow-wave activity (SWA). Our hypothesis was that learning is accompanied by a change in the components of CAP characterized by SWA (0.5-2.5Hz), i.e. its A1 subtypes. For this reason, in the present study we evaluated sleep recordings obtained in 10 healthy young normal subjects (mean age 25.8+/-1.8 years) who were asked to perform a motor learning task just before going to sleep. Sleep EEG was recorded for 2h and subjects were also tested after the night following the rotation task. Sleep stages and CAP (classified into three subtypes: A1, A2, and A3) were identified in the first hour of each recording. We found a significant increase in the number of CAP A1 subtypes per hour of NREM sleep on the night following the rotation test; the correlation between the change in A1 index and the post-sleep performance improvement after the rotation task was positive. These results confirm our hypothesis that CAP slow components are modified by a learning task during the day preceding sleep and support the idea that these components may play a role in sleep-related cognitive processes.

Ipsilateral motor activation during unimanual and bimanual motor tasks

OBJECTIVE To test for the presence and possible asymmetry of ipsilateral motor activation during unimanual and bimanual motor tasks. METHODS Twelve right-handed healthy subjects underwent motor evoked potential (MEP) measurement of one hand (target-hand) while the other hand (task-hand) performed different motor tasks. The target-hand was either at rest (first experiment) or performed a Perdue PegBoard task (second experiment). The task-hand was either at rest, performed a simultaneous pegboard task, or rotated a coin (second experiment). RESULTS In the first experiment, the motor task resulted in significant increase in MEP area in the target-hand, regardless which hand was the task-hand, with a greater increase when the left hand was the task-hand. In the second experiment, ipsilateral motor activation was not present for either hand, however, when the right hand was the task-hand, performance of continuous coin rotation by the right hand resulted in a significant decrease in the MEP area of the left hand. CONCLUSIONS Hemispheric asymmetry and task-dependence of ipsilateral motor cortex activation supports the postulate that motor activity may start bilaterally with subsequent interhemispheric inhibition. Furthermore, in right-handers, the left motor cortex is either more active in ipsilateral hand movements or exerts more effective inhibitory control over the right motor cortex than vice versa. SIGNIFICANCE We suggest that hemispheric asymmetry in ipsilateral motor control is a factor in determining motor dominance in right-handed individuals.

Aceruloplasminaemia with progressive atrophy without brain iron overload: treatment with oral chelation

Background: Hereditary aceruloplasminaemia is a disorder of iron metabolism that is characterised by iron accumulation in the brain and other visceral organs. In previously reported cases, individuals with the disorder were noted to have evidence of iron accumulation in the brain. Oral chelating agents have not been used in neurological diseases of iron metabolism. Methods: A 54-year-old woman who presented with ataxia, lower extremity spasticity and chorea was evaluated for evidence of the source of neurological dysfunction. Results: Blood studies revealed no detectable ceruloplasmin. Marked iron overload was defined by a liver biopsy, which showed a variegated pattern consistent with a primary cause of iron overload. Review of MRI scans showed progressive brain atrophy without visible iron accumulation occurring over a 5-year period. The history suggested that neurodegeneration was coincident with aggressive oral iron replacement. Oral chelation improved many symptoms. Conclusions: Our findings in this patient suggest that disorders of iron transport such as aceruloplasminaemia can be a cause of neurological symptoms such as chorea and cognitive decline, as well as progressive neurodegeneration in the absence of visible iron on MRI scans. We found that oral iron chelation was effective at improving symptoms.

Effects of NREM sleep instability on cognitive processing.

OBJECTIVE Cyclic alternating pattern (CAP) A1 subtypes, characterized by high-voltage slow waves, are generated by the frontal cortex and are suspected to have a role in cognitive processing during NREM sleep. Conversely, CAP A2 and A3 subtypes are characterized by variable amounts of rapid EEG potentials arising from the parietal-occipital areas and often coincide with arousals. We tested the hypothesis that CAP subtypes differentially correlate with cognitive functions. SUBJECTS AND METHODS Eight healthy participants were recruited. Two nocturnal polysomnography studies and a series of neuropsychological tests were obtained in the subjects during the morning and afternoon of the first day and on the morning of the second day. RESULTS In agreement with our original hypothesis, we found that CAP A1 subtypes were correlated with better neuropsychological functioning the day after, for verbal fluency, working memory, and both delayed recall and recognition of words. These same neuropsychological test results were found to be negatively correlated with CAP A2 subtypes. CAP A3 subtypes were negatively correlated with the Trial Making test Parts A and B. CONCLUSIONS The results suggest that CAP A1 might be related to better cognitive functioning, whereas CAP A2 and A3 correlated with worse cognitive functioning. Further studies are needed to better understand how CAP influences cognitive performance, especially frontally-dependent functions and memory.

Sleep Polygraphic Study of Children and Adolescents With Narcolepsy/Cataplexy

The alterations of the Cyclic Alternating Pattern (CAP) recently found in narcoleptic adult patients suggest the presence of an impaired modulation of the fluctuations of the arousal level during their non-rapid eye movement (NREM) sleep, possibly because of the persistence of neurophysiological mechanisms typical of rapid eye movement (REM) sleep. The same mechanism might play a role in the occurrence of leg movement (LM) activity during sleep characterized by low levels of periodicity. The aim of this study was to evaluate CAP and sleep LM activity in a group of children and adolescents with narcolepsy, to interpret the results under a developmental point of view and integrate this new information with data already available for adults. Thirteen young patients with narcolepsy/cataplexy were consecutively recruited for this study, together with 13 age- and sex-matched normal controls. Nocturnal polysomnography was carried out after a night of adaptation in a sleep laboratory room; sleep stages, CAP, and LMs were scored and evaluated following standard criteria. Narcoleptic patients showed shorter sleep onset and REM sleep latency, higher number of stage shifts and awakenings per hour of sleep, and higher percentage of wakefulness after sleep onset; CAP rate was found to be decreased in all NREM sleep stages (in particular CAP A1 subtypes) in narcoleptic patients who also showed significant higher values of all types of LMs (periodic or isolated), during both REM and NREM sleep; however, the most evident differences were found during REM sleep. The results of this study confirm that the sleep microstructure and LM activity changes observed in adulthood are already present and detectable in childhood and might have a role in the already known impaired prefrontal functioning of these subjects. The well-established orexin deficiency might be the unifying factor playing a major role in the modulation of CAP and LMs during sleep in children and adolescents with narcolepsy/cataplexy.

The effects of experimental sleep fragmentation on cognitive processing

OBJECTIVE The primary objective of this study was to characterize the association between cyclic alternating pattern (CAP) and neurocognitive performance in a group of normal subjects before and after two nights of experimentally-induced sleep fragmentation. SUBJECTS AND METHODS Fifteen healthy subjects underwent one night of uninterrupted and two sequential nights of experimental sleep fragmentation achieved by auditory and mechanical stimuli. Eight subjects were re-examined using a similar paradigm with three nights of uninterrupted sleep. Sleep was polygraphically recorded and CAP analysis was performed for all recordings. A battery of neurocognitive tests was performed for spatial attention, inhibition of return, mental rotation, and Stroop color word test in the afternoon following the first and third night of sleep under fragmented and non-fragmented conditions. RESULTS With sleep fragmentation, the percentage of slow-wave sleep was dramatically reduced and there was a twofold increase in total CAP rate across all NREM sleep stages. Moreover, the number of all CAP A subtypes/hour of sleep (index) was significantly increased. Total CAP rate during the non-fragmented night correlated with reaction times. Similarly, the percentages of A1 and A3 subtypes were negatively and positively correlated with reaction times, respectively. Of the neurocognitive test battery, however, only values obtained from some subtests of the mental rotation test showed a significant improvement after sleep fragmentation. CONCLUSIONS The results of this study suggest that CAP A1 subtypes are associated with higher cognitive functioning, whereas CAP A3 subtypes are associated with lower cognitive functioning in young healthy subjects. The lack of cognitive functioning impairment after sleep fragmentation may be due to persistence and even enhancement of transient slow-wave activity contained in CAP A1 subtypes which also caused a significant enhancement of the EEG power spectrum in the lower frequencies.

Effects of Donepezil on Verbal Memory After Semantic Processing in Healthy Older Adults

ObjectiveTo learn if acetylcholinesterase inhibitors alter verbal recall by improving semantic encoding in a double-blind randomized placebo-controlled trial. BackgroundCholinergic supplementation has been shown to improve delayed recall in adults with Alzheimer disease. With functional magnetic resonance imaging, elderly adults, when compared with younger participants, have reduced cortical activation with semantic processing. There have been no studies investigating the effects of cholinergic supplementation on semantic encoding in healthy elderly adults. MethodTwenty elderly participants (mean age 71.5, SD±5.2) were recruited. All underwent memory testing before and after receiving donepezil (5 mg, n=11 or 10 mg, n=1) or placebo (n=8) for 6 weeks. Memory was tested using a Levels of Processing task, where a series of words are presented serially. Subjects were either asked to count consonants in a word (superficially process) or decide if the word was “pleasant” or “unpleasant” (semantically process). ResultsAfter 6 weeks of donepezil or placebo treatment, immediate and delayed recall of superficially and semantically processed words was compared with baseline performance. Immediate and delayed recall of superficially processed words did not show significant changes in either treatment group. With semantic processing, both immediate and delayed recall performance improved in the donepezil group. ConclusionsOur results suggest that when using semantic encoding, older normal subjects may be aided by anticholinesterase treatment. However, this treatment does not improve recall of superficially encoded words.

Anxiety and depression severity are related to right but not left onset Parkinson's disease duration

Depression and anxiety have both been associated with relative left frontal hypoactivation and the motor symptoms of Parkinsons disease typically begin in a lateral or asymmetrical fashion. Hence, PD patients with right hemibody onset may experience heightened depression and anxiety. However, research is mixed regarding whether right or left hemibody onset PD is associated with elevated levels of depression and anxiety. This literature, though, has not considered the potential moderating variable of disease duration. We hypothesized that disease duration would be positively correlated with measures of depression and anxiety in right but not left hemibody onset PD patients. The results indicated that scores on the Geriatric Depression Scale, Beck Depression Inventory-II, and the State Trait Anxiety Scale - State correlated positively with disease duration, but only in the right hemibody onset group of PD patients. Thus, right hemibody onset PD is associated with more severe depressive and anxiety symptoms, but only when disease duration is considered.

Creativity in Parkinson's disease as a function of right versus left hemibody onset.

OBJECTIVE Creativity is heavily dependent on divergent thinking and divergent thinking appears to be strongly dependent on fontal lobe function. Since patients with Parkinsons disease (PD) often have evidence of frontal lobe dysfunction we wanted to learn if these patients have a reduction of creativity, as well as learning if the side of onset (right versus left) influences the type (verbal versus visuospatial) of decrement in creativity. DESIGN Participants of this study were patients with right (RHO) or left (LHO) onset PD as well as matched controls. All subjects were given the Abbreviated Torrance Test of Creative Thinking for Adults (ATTA), a widely used test to assess creativity that examines Fluency, Originality, Flexibility and Elaboration. Subjects were also assessed with the Controlled Word Association Test (COWAT). RESULTS/CONCLUSIONS When compared to controls the patients with RHO, but not LHO, had a decrease of verbal creative fluency. Patients with PD often have a decrease on the COWAT, but performance on the COWAT did not differ between the RHO and the LHO patients. This suggests that patients with PD who have RHO have a decrease in verbal creativity and this decrement does not appear to be related to decreased fluency.