CSF lactate levels, τ proteins, cognitive decline: a dynamic relationship in Alzheimer's disease.

OBJECTIVES: To investigate, in patients with Alzheimer's Disease (AD), the possible interplay linking alteration of neuronal energy metabolism, as measured via cerebrospinal fluid (CSF) lactate concentration, to severity of AD neurodegenerative processes and impairment of cognitive abilities. METHODS: In this study we measured and correlated CSF lactate concentrations, AD biomarker levels (τ-proteins and ß-amyloid) and Mini-Mental State Examination (MMSE) score in a population of drug-naïve patients with AD ranging from mild (MMSE≥21/30) to moderate-severe (MMSE<21/30) cognitive decline. They were compared to healthy controls and patients with vascular dementia (VaD). RESULTS: Patients with AD (n=145) showed a significant increase of CSF lactate concentration compared to controls (n=80) and patients with VaD (n=44), which was higher in mild (n=67) than in patients with moderate-severe AD (n=78). Moreover, we found, in either the whole AD population or both subgroups, a CSF profile in which higher CSF levels of t-τ and p-τ proteins corresponded to lower concentrations of lactate. CONCLUSIONS: We verified the occurrence of high CSF lactate levels in patients with AD, which may be ascribed to mitochondria impairment. Hypothesising that τ proteins may exert a detrimental effect on the entire cellular energy metabolism, the negative correlation found between lactate and τ-protein levels may allow speculation that τ toxicity, already demonstrated to have affected mitochondria, could also impair glycolytic metabolism with a less evident increase of lactate levels in more severe AD. Thus, we suggest a dynamic relationship between neuronal energy metabolism, τ proteins and cognitive decline in AD and propose the clinical potential of assessing CSF lactate levels in patients with AD to better define the neuronal brain metabolism damage.

Restless legs syndrome and post polio syndrome: a case-control study.

BACKGROUND AND PURPOSE: The aim was to investigate the prevalence of restless legs syndrome (RLS), fatigue and daytime sleepiness in a large cohort of patients affected by post polio syndrome (PPS) and their impact on patient health-related quality of life (HRQoL) compared with healthy subjects. METHODS: PPS patients were evaluated by means of the Stanford Sleepiness Scale and the Fatigue Severity Scale (FSS). The Short Form Health Survey (SF-36) questionnaire was utilized to assess HRQoL in PPS. RLS was diagnosed when standard criteria were met. Age and sex matched healthy controls were recruited amongst spouses or friends of PPS subjects. RESULTS: A total of 66 PPS patients and 80 healthy controls were enrolled in the study. A significantly higher prevalence of RLS (P < 0.0005; odds ratio 21.5; 95% confidence interval 8.17-57) was found in PPS patients (PPS/RLS+ 63.6%) than in healthy controls (7.5%). The FSS score was higher in PPS/RLS+ than in PPS/RLS- patients (P = 0.03). A significant decrease of SF-36 scores, including the physical function (P = 0.001), physical role (P = 0.0001) and bodily pain (P = 0.03) domains, was found in PPS/RLS+ versus PPS/RLS- patients. Finally, it was found that PPS/RLS+ showed a significant correlation between International Restless Legs Scale score and FSS (P < 0.0001), as well as between International Restless Legs Scale score and most of the SF-36 items (physical role P = 0.0018, general health P = 0.0009, vitality P = 0.0022, social functioning P = 0.002, role emotional P = 0.0019, and mental health P = 0.0003). CONCLUSION: Our findings demonstrate a high prevalence of RLS in PPS, and that RLS occurrence may significantly influence the HRQoL and fatigue of PPS patients. A hypothetical link between neuroanatomical and inflammatory mechanisms in RLS and PPS is suggested.

Low frequency stimulation of the nucleus tegmenti pedunculopontini increases cortical metabolism in parkinsonian patients.

BACKGROUND AND PURPOSE: To evaluate the effects of 25-Hz deep brain stimulation of the nucleus tegmenti pedunculopontini (PPTg) on brain metabolic activity. METHODS: Six patients with Parkinson's disease (PD) who had bilateral stereotactic implantation of PPTg at least 12 months prior to evaluation were included in our study. All underwent, in separate sessions, 18-FDG-PET in core assessment programme for intra-cerebral transplantation as well as motor evaluation [Unified Parkinson's disease rating scale (UPDRS)--Section III] and a battery of cognitive testing. RESULTS: PPTg-ON (low bipolar contacts, 25 Hz) promoted a significant increase of glucose utilization in bilateral prefrontal areas including dorsolateral prefrontal cortex (DLPFC, BA9), orbito-frontal cortex (BA47), anterior cingulate (BA 25-32), superior frontal gyrus (BA 10) and supramarginal gyrus (BA40); a significant increase of uptake and consumption of FDG also occurred in the left ventral striatum, left subgyral (BA 46), right insula (BA 13) and right superior temporal gyrus (BA 22). PPTg-ON was associated with a significant decrease of glucose utilization in the left cerebellar anterior lobe (culmen) and right cerebellar posterior lobe (declive). In the same patients, PPTg-ON improved delayed recall (P < 0.05) and executive functions whilst the UPDRS revealed a modest (-21%) and variable treatment effect. CONCLUSIONS: Low frequency stimulation of PPTg, a sub-region of the pedunculopontine nucleus complex, causes a minor motor benefit but a peculiar profile of cognitive improvement associated with a significant increase in FDG consumption in both prefrontal areas and mono-lateral ventral striatum. These data are consistent with multiple limbic and/or associative domains modulated by PPTg stimulation in our patients with PD.

Deep brain stimulation of CM/PF of thalamus could be the new elective target for tremor in advanced Parkinson's Disease?

Aim of this study was to investigate whether Deep Brain Stimulation (DBS) of the Centre Median Nucleus/Parafascicular (CM/PF) Complex is useful in reducing extrapyramidal symptoms in advanced Parkinson's Disease (PD) patients. In particular, we compared the action of CM/PF and subthalamic nucleus (STN) DBS on resting hand tremor using EMG surface of ulnar and radial right-hand muscles. Our results show that C/M DBS is very effective in reducing tremor, indicating this complex as a new target in advanced PD patients.

Deep brain stimulation in Parkinson's disease patients: biochemical evidence.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen--PUT--and GPi) and in a thalamic relay nucleus, the anteroventral thalamus (VA). In six advanced PD patients undergoing surgery, microdialysis samples were collected from GPi, PUT and VA before, during and after one hour of STN-DBS. cGMP was measured in the GPi and PUT as an index of glutamatergic transmission, whereas GABA was measured in the VA. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in the VA (-25%). Simultaneously, cGMP extracellular concentrations were enhanced in the PUT (+200%) and GPi (+481%). DBS differentially affects fibers crossing the STN area: it activates the STN-GPi pathway while inhibiting the GPi-VA one. These findings support a thalamic dis-inhibition, as the main responsible for the clinical effect of STN-DBS. This, in turn, re-establishes a more physiological level of PUT activity.

Sleep episodes and daytime somnolence as result of individual susceptibility to different dopaminergic drugs in a PD patient: a polysomnographic study.

The association between excessive daytime somnolence (EDS) and idiopathic Parkinson's disease (PD) is often reported but still debated. The possible role of antiparkinsonian therapy or primarily of PD on excessive diurnal sleepiness is controversial. We describe the case of a 61-year-old patient affected by PD who experienced sleep episodes (SE) occurring during pramipexole plus L-Dopa therapy. Polysomnographic sleep studies and subjective evaluations of daytime sleepiness (Epworth Sleepiness Scale) were carried out under administration of pramipexole plus L-Dopa, L-Dopa monotherapy and cabergoline plus L-Dopa. The polysomnography revealed two sleep events during pramipexole plus L-Dopa. Moreover, the polysomnographic data showed an increase of both diurnal and nocturnal sleep under pramipexole plus L-Dopa compared with cabergoline plus L-Dopa and L-Dopa as monotherapy. In addition, while Epworth Sleepiness Scale (ESS) Score showed a mild sleepiness under pramipexole (ESS score=11), ESS scores were normal under both L-Dopa and cabergoline plus L-Dopa. Sleep episodes also disappeared under both L-Dopa and cabergoline plus L-Dopa (2- and 12-month follow-up). We hypothesize that an individual susceptibility to specific antiparkinsonian drug may play a significant role in the genesis of sleepiness in our PD patient.

Visual alterations in de novo Parkinson's disease: pattern electroretinogram latencies are more delayed and more reversible by levodopa than are visual evoked potentials.

There are increased latencies of pattern-reversal visual evoked potentials (VEPs) and electroretinograms (PERGs) in Parkinson's disease (PD) patients who have not received therapy. This study aimed to evaluate whether these delays are present in the early stage of PD and whether they are dopamine-sensitive. The results show that both PERG P50 and VEP P100 latencies are increased (p < 0.0001) in a group of patients with de novo PD (13 subjects; 13.3 +/- 5.6 months' mean disease duration) before therapy in comparison with an age-matched control group (eight subjects). A larger latency increase (9.9% at the 47% contrast level and 7.8% at the 96% contrast level) was present in PERG recordings than in VEPs (6.2% at the 47% contrast level and 3.9% at the 96% contrast level). Levodopa therapy produced recovery of both PERG and VEP latency increases at both contrast levels, but only the PERG recovery at 47% of contrast was statistically significant. Before therapy, five eyes from PD patients showed no reproducible PERG at the 47% contrast level although the simultaneously recorded VEP was present. Both potentials were recordable in the same eyes at the 96% contrast level. During therapy, four of those five eyes showed a clear PERG even at the 47% contrast level. We conclude that, using an adequate midspatial frequency, both VEPs and PERGs are delayed even in the early stage of PD, and that PERGs are more sensitive if low contrast (47%) is used. The larger alterations, as well as the larger recovery during levodopa therapy, seem to correlate the PERG response more than the VEP response to dopaminergic transmission.

Emotional processing in Parkinson's disease. A study using functional transcranial doppler sonography.

This study evaluated the use of transcranial Doppler ultrasonography for detecting selective changes in cerebral blood flow velocity during emotional processes. The aim was to investigate the possibility of obtaining functional information on the neuropsychology of emotions in patients with Parkinson's disease (PD). For this reason, blood flow velocity changes were investigated in both middle cerebral arteries (MCA) during a rest condition and when viewing non emotional (tasks 1 and 3) and emotional (task 2) slide sequences. The study included 12 PD patients and 12 healthy subjects. All patients were in treatment with levodopa or dopamine agonist. Investigation of PD patients was performed during an on-phase. The three tasks produced significantly different effects on the right and left side in the PD patients compared with the control group. During the two non emotion-related tasks the increase of mean flow velocity (MFV) compared with the basal values was similar in the two middle cerebral arteries in both groups [(PD Patients: Task 1: left MCA = 3.95 % 2.2, Right MCA = 4.33 % +/- 2.3, Task 3: left MCA = 3.04 % +/- 1.9, Right MCA = 2.71 % +/- 2.2) (control group: Task 1: left MCA = 4.57 % +/- 1.4, Right MCA = 4.46 % +/- 1.7, Task 3: left MCA = 2.32 % +/- 0.9, Right MCA = 2.52 % +/- 1.2)] The negative emotional task was accompanied by a significantly higher increase in the right (10.53 % +/- 3.2) than in the left middle cerebral artery (4.52 % +/- 1.51) only in the control group. The PD patients showed a bilateral and symmetrical increase of MFV (left MCA = 4.28 % +/- 2.3 and right MCA 5.77 % +/-3.8). To determine whether there was a dysfunction in cerebrovascular reactivity and a deficit in the ability to activate both hemispheres in response to non emotion-related stimuli in the PD patients, the protocol study included a cerebrovascular reactivity test to apnea, a motor task (thumb-to-finger opposition), a cognitive task (word fluency and visual discrimination of objects), performed by both patients and controls. The pattern of MFV changes during these tasks was not statistically significantly different in the two experimental groups. In order to evaluate the possible influence of drug treatment on cerebrovascular reactivity, seven patients were also evaluated during an off-phase, after a 48-hour wash-out period. Changes in MFV during every task were similar to that observed during the on-phase. These findings show the possibility of obtaining specific functional information from bilateral transcranial Doppler and suggest the selective and specific deficit of PD patients in emotional processing.

Parkinson's disease changes the balance of onset and offset visual responses: an evoked potential study.

OBJECTIVES: We investigated whether the transient pattern onset and offset visual evoked potential (VEP) can distinguish between patients with Parkinson's disease (PD) and normal subjects. METHODS: Two horizontal sinusoidal gratings differing in spatial frequency, i.e. 1 and 4 cycles per degree, were presented to 17 patients with PD and 16 age-matched control subjects. We analyzed the responses in the time-domain and measured the latencies and amplitudes of N1 and P1 to the onset and the offset of the stimulus; we also derived the measures of offset N1 and P1 amplitude responses 'normalized' to onset N1 and P1 amplitude values, respectively (amplitude ratios). RESULTS: Absolute and normalized offset P1 amplitude is a distinguishing feature of PD patients from controls. Offset P1 amplitude was significantly larger in PD patients than in controls, particularly to the lower spatial frequency stimulus (P<0.01 for absolute and P<0.001 for normalized values, respectively). CONCLUSIONS: We conclude that the pattern onset/offset VEP amplitude provides a simple measure to evaluate visual processing deficits in PD and could contribute to an understanding of the pathophysiology of these changes.

A mixed D1 and D2 antagonist does not replay pattern electroretinogram alterations observed with a selective D2 antagonist in normal humans: relationship with Parkinson's disease pattern electroretinogram alterations.

The human retina produces a tuned response to stimuli of increasing spatial frequency reversed at a steady state. The peak amplitude response, at medium spatial frequencies, is decreased in Parkinson's disease and in normal subjects (n = 18) treated with a D2 dopaminergic antagonist (l-sulpiride). Here, we report that a mixed D1-D2 receptor antagonist (haloperidol) in normal subjects (n = 18) does not produce an amplitude decrease of medium spatial frequencies (SFs) responses but it decreases low-frequency response. It could argued that the increased dopamine release produced by the presynaptic D2 antagonistic action of haloperidol is subsequently counteracted at postsynaptic level by its D1 antagonistic effect, producing a net counterbalance at medium SFs. These data suggest that the two dopamine receptors may play different roles in the retinal function and in the origin of visual alterations in Parkinson's disease.

Different TMS patterns of intracortical inhibition in early onset Alzheimer dementia and frontotemporal dementia.

OBJECTIVE: To investigate putative changes in cortical excitability of patients affected by early-onset mild dementia by means of transcranial magnetic stimulation (TMS) and to verify whether a peculiar neurophysiological profile may contribute to characterise Alzheimer's disease (AD) vs frontotemporal dementia (FTD). METHODS: Motor threshold and intracortical inhibition (ICI) and facilitation (ICF) after paired-pulse TMS (inter-stimulus intervals from 1 to 20 ms) were studied in two groups of early-onset demented patients with a neuropsychological profile suggestive of AD (n = 12) and FTD (n = 8). Twelve age-matched healthy subjects were considered as control group. In both patient groups, recordings were performed before and after a single oral dose of 4 mg galantamine. RESULTS: No significant difference in motor threshold was observed among the three studied groups. On the contrary, early-onset AD showed a significant reduction of ICI compared to control group, no changes were detected in FTD patients. No significant changes in ICF were found between both patient groups and healthy subjects. The acute administration of galantamine reversed the modified ICI in AD group. CONCLUSIONS: The differential pattern of ICI exhibited by early-onset AD vs FTD in the early stage of disease may represent a non-invasive, reproducible electrophysiological tool, which may contribute to early differential diagnosis and, possibly, to monitor therapeutic effectiveness. SIGNIFICANCE: The present results support the possibility that subtle, early modifications in intracortical circuitry features AD, but not FTD patients.

Subdyskinetic apomorphine responses in globus pallidus and subthalamus of parkinsonian patients: lack of clear evidence for the 'indirect pathway'.

OBJECTIVES: Previous studies suggested that the hypo-activity of the external pallidus (GPe) might drive the hyper-activity of subthalamic neurons, which underlies the cardinal symptoms of Parkinson's disease. We have challenged this view, based on the so-called 'indirect pathway', by recording apomorphine effects from both structures of parkinsonian patients, at rest and during passive movements. METHODS: We performed single-unit recordings from external pallidus (GPe), internal pallidus (GPi) and subthalamic nucleus (STN) during the stereotactic neurosurgery aimed to implant deep brain stimulating electrodes in GPi or STN. First, we verified the firing frequency of each structure in off-state conditions. Then, therapeutic, subdyskinetic concentrations of the dopaminergic agonist apomorphine was delivered to assess each nucleus response. RESULTS: The firing rate of STN averaged about 40 Hz; a large proportion (75%) of STN units exhibited marked responsiveness to passive movements. Apomorphine reduced the firing discharge of parkinsonian STN in all cells, although electrophysiological recovery was usually incomplete. Movement-related activity was also dramatically reduced. In contrast, apomorphine failed to modify the firing frequency of GPe, despite the amelioration of hypo-kinetic symptoms and the simultaneous inhibition of GPi firing discharge. CONCLUSIONS: We demonstrate that part of the models on basal ganglia circuitry needs to be revised. The re-balancing of STN hyper-activity, when patients benefit from dopaminergic therapy, is not due to an increased input from GPe, but, instead, due to changes in STN intrinsic firing properties and/or modulation of glutamatergic inputs.

Deep brain stimulation of both subthalamic nucleus and internal globus pallidus restores intracortical inhibition in Parkinson's disease paralleling apomorphine effects: a paired magnetic stimulation study.

OBJECTIVE: We investigated the effect of bilateral subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) on intracortical inhibition (ICI) in patients with advanced Parkinson's disease (PD). METHODS: The activity of intracortical inhibitory circuits was studied in 4 PD patients implanted with stimulating electrodes both in STN and GPi by means of paired-pulse transcranial magnetic stimulation, delivered in a conditioning-test design at short (1-6 ms) interstimulus intervals (ISI). The effect of apomorphine on the same PD patients was also investigated. RESULTS: We observed that implanted PD patients showed a significant increase in ICI during either bilateral STN or GPi DBS at 3 ms ISI, and during bilateral STN DBS at 2 ms ISI in comparison to their off DBS condition. The same statistical improvement was observed during apomorphine infusion at 3 and 2 ms ISI. In each condition, the electrophysiological changes were associated with a significant clinical improvement as measured by the Unified Parkinson's Disease Rating Scale motor examination. CONCLUSIONS: These results are consistent with the hypothesis that basal ganglia DBS can mimic the effects of pharmacological dopaminergic therapy on PD patients cortical activity. We propose that in PD patients, the basal ganglia DBS-induced improvement of ICI may be related to a recovery in modulation of thalamo-cortical motor pathway.

The effect of deep brain stimulation on the frontal N30 component of somatosensory evoked potentials in advanced Parkinson's disease patients.

OBJECTIVES: In the present study we investigated whether in advanced Parkinson's disease (PD) patients the frontal component of short somatosensory evoked potentials (SEPs) to median nerve stimulation may be modified by basal ganglia deep brain stimulation (DBS). METHODS: We recorded the SEPs in 6 PD patients undergoing bilateral functional neurosurgery in the internal globus pallidus (GPi) (4 patients) and in the nucleus subthalamicus (STN) (two patients) during ineffective and effective bilateral BDS. Pre-operatively, the SEPs were also recorded in off therapy and during apomorphine infusion. RESULTS: From the evaluation of the latency and the amplitude characteristics of the major parietal (N20 and P25) and frontal (N30) components, we observed that whereas the parietal waves did not vary in any condition, the N30 potential showed a remarkable amplitude increase during apomorphine as well as during effective bilateral GPi or STN DBS. Furthermore, after the stimulators were turned off we noticed that the N30 amplitude potential progressively faded almost in parallel with the attenuation of DBS clinical effects. CONCLUSIONS: Our results lead to the conclusion that the bilateral DBS of both GPi and STN is really effective in producing a selective increase of frontal N30 amplitude probably improving the supplementary motor area functional activity, but these results do not clarify whether this amelioration is due to a central or a 'long loop' mechanism.

An electrophysiological study of D2 dopaminergic actions in normal human retina: a tool in Parkinson's disease.

A peculiar deficit of electrophysiological retinal responses to pattern reversal grating stimuli has been reported in Parkinson's disease (PD) patients. A similar abnormality has been reproduced by means of non-selective dopaminergic antagonists in normal humans. Aim of this study was to verify, by means of a selective D2 antagonist (sulpiride) administered to normal subjects, whether a D2 blockade affects the visual electrophysiological performances with the same trend as observed in PD patients. Patterns electroretinogram (PERG) responses to 1 cycle per degree (c/d) of spatial frequency at 1 (transient) and 7.5 (steady state) Hz of temporal modulation of a square-wave grating pattern reversal have been recorded in 19 healthy volunteers before and after the administration of 100 mg i.m. of sulpiride. The data are consistent for the following conclusion: a selective D2 antagonist reduces steady state and delays transient retinal responses as expected for a PD mimicking agent.

Increasing doses of l-sulpiride reveal dose- and spatial frequency-dependent effects of D2 selective blockade in the human electroretinogram.

The amplitude and phase of the second harmonic (15 Hz) of the electroretinographic responses to three different spatial frequency grating stimuli (0.25, 1 and 4 c/deg), reversed at 7.5 Hz, were studied i normal human subjects, before and 30 min after the systemic administration of three doses (0.071, 0.357 or 1.428 mg/kg) of a selective D2 blocker, l-sulpiride, to three populations of 18, 19, or 20 subjects. The effect of the drug on the pattern electroretinogram (PERG) was clearly dose-dependent, being greatest on the responses to 4 c/deg. The mean decrease in second harmonic amplitude was -13.8% after 0.071 mg/kg of l-sulpiride, -23.5% after 0.357 mg/kg and -28.5% after 1.428 mg/kg. The last two variations were significant at P < 0.01 and P < 0.01 respectively. These data suggest that a dose-dependent effect on the human retinal response to 4 c/deg stimuli exists, probably mediated by a coupling between l-sulpiride and D2 receptors. Lastly, our data suggest that D2 receptors may play an important role in the pathophysiology of visual dysfunction in Parkinson's disease, that has been described to be more significant at medium spatial frequency (2-5 c/deg).

N30 wave amplitude of somatosensory evoked potentials from median nerve in Parkinson's disease: a pharmacological study.

We studied N20 and N30 waves of Somatosensory Evoked Potentials from median nerve stimulation in different pharmacological conditions. N30 wave amplitude was decreased in 33 parkinsonians without therapy in comparison with a group of age-matched normal subjects. In a group of 19 parkinsonians, N30 wave amplitude was significantly augmented during apomorphine infusion and less evidently, but still significantly, during chronic 1-dopa therapy. The administration of an oral dose of haloperidol in 11 normals did not affect significantly the studied parameters. The infusion of apomorphine in 6 psychotic patients with extrapyramidal symptoms secondary to long-term treatment with neuroleptics, determined, together with a clear-cut clinical amelioration, a significant increase of N30 amplitude and N30/N20 ratio. Possible pathophysiological hypothesis of such electrophysiological modifications are discussed.

P3 components evoked by unilateral and bilateral somatosensory stimulation: normative data for the study of neglect syndrome.

Latency and amplitude of an "odd-ball" somatosensory P3 component evoked either by unilateral or bilateral somatosensory target stimulation, were measured in 15 healthy right-handed subjects (age range 42-79 years) in order to obtain normative data useful for studying the neglect syndrome. The bilateral stimulation protocol was designed to investigate the tactile extinction phenomenon. P3 waves were recorded from nine electrodes. A three-way Anova showed that mean P3 latency on the whole scalp following unilateral stimulations, regardless of side (i.e. right or left stimulations), was significantly longer than that observed after bilateral stimulation. Both "early" and "late" peaks were usually observed in P3 complex. The bilateral modality stimulation showed a more evident "early" peak than the two unilateral stimulations. No significant mean P3 amplitude differences were observed on the whole scalp between bilateral and unilateral stimulations. No significant amplitude differences were observed either for the right or the left hemisphere. The reported latency decrease in the bilateral target stimulation may be a valuable cue for studying possible modifications in patients affected by neglect.