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.

Tetrabenazine improves levodopa-induced peak-dose dyskinesias in patients with Parkinson's disease.

Since levodopa-induced peak dyskinesias (LIDs) may reflect, in part, a disproportionate phasic release of dopamine from synaptic vesicles, we examined the ability of the vesicular depletor tetrabenazine (TBZ) to reduce LIDs in 10 dyskinetic advanced Parkinson's disease (PD) patients. After basal evaluation, the patients received, through a slow titration, oral TBZ twice a day for six weeks (up to 50 mg daily) before being re-assessed after a challenge with levodopa. The primary outcome measure was the change in the Unified Parkinson's Disease Rating Scale (UPDRS) dyskinesia score (items 32 to 34). TBZ was well tolerated. A clear treatment effect on LIDs emerged (up to 45%, p<0.05). In two patients a little worsening of motor performance necessitated an increase of the antiparkinsonian therapy, which did not worsen peak-dose LIDs. The patients experienced a clear benefit in terms of their quality of life. In this open-label pilot study, orally administered TBZ resulted in objective and subjective improvements in LIDs. Larger pharmacological studies are in progress.

Different patterns of cardiac sympathetic denervation in tremor-type compared to akinetic-rigid-type Parkinson's disease: molecular imaging with ¹²³I-MIBG.

The aim of this study was to evaluate the correlation between the clinical motor phenotypes of Parkinson's disease (PD) and ¹²³I-MIBG myocardial uptake. In total, 53 patients with PD [31 males and 22 females, mean age 62±10 years; 19 Hoehn & Yahr (H&Y) stage 1, 9 stage 1.5, 15 stage 2 and 10 at stage 3] were examined and subdivided into different clinical forms on the basis of dominance of resting tremor (n=19, TDT) and bradykinesia plus rigidity (n=34, ART). This status was correlated with the semi-quantitative analysis of ¹²³I-MIBG myocardial uptake. An age-matched control group of 18 patients was recruited (8 males and 10 females, mean age 62.4±16.3 years). ¹²³I-MIBG myocardial uptake significantly correlated with disease duration in early (r²=0.1894; P=0.0028) and delayed images (r²=0.1795; P=0.0037) in PD patients, while no correlation was found when considering age at examination, UPDRS III motor examination section score and H&Y score. PD patients showed a reduced ¹²³I-MIBG myocardial uptake compared to the control group in early (P=0.0026) and delayed images (P=0.0040), and ¹²³I-MIBG myocardial uptake was significantly lower in delayed images in TDT patients compared with ART patients (P=0.0167). A decrease was detected in the heart-to-mediastinum (H/M) ratio in delayed images compared to that of the early images in TDT patients (P=0.0040) and in the whole PD population (P=0.0012), while no differences were found in ART patients (P=0.1043). The results of the present study revealed that the cardiac sympathetic system is more severely impaired in TDT than in ART patients and ¹²³I-MIBG molecular imaging has the potential help in improving therapeutic planning in these patients.

Different patterns of nigrostriatal degeneration in tremor type versus the akinetic-rigid and mixed types of Parkinson's disease at the early stages: molecular imaging with 123I-FP-CIT SPECT.

The various associations of motor and non-motor symptoms, the onset of motor complications, the cognitive disorder's appearance and other factors make Parkinson's disease (PD) a heterogeneous syndrome with multiple phenotypes. The necessity of discriminating between different forms of PD could have a role in understanding the pathophysiology of extrapyramidal signs with clinical implications. The aim of this study was to evaluate if there is a relationship between the clinical motor phenotypes of PD and the scintigraphic pattern of 123I-FP-CIT single photon emission computed tomography (SPECT). We examined 47 patients with early idiopathic PD (25 males; 22 females; mean age 58±2 years) and subdivided them in different clinical forms on the basis of dominance of resting tremor (n=20), bradykinesia plus rigidity (n=20) and the presence of both clinical signs [mixed type (MT, n=7)]. We correlated this status with the semi-quantitative analysis of SPECT with 123I-FP-CIT. Tremor type patients showed a lower reduction of 123I-FP-CIT uptake compared to akinetic-rigid type patients in contralateral caudate (P=0.0139) and putamen (P=0.0028) nuclei. 123I-FP-CIT uptake was higher in the ipsilateral caudate (P=0.0050) and putamen (P=0.0012) of tremor type patients compared to akinetic-rigid type patients. Comparisons of the striatal uptake in the tremor type and akinetic-rigid type patients with the MT patients revealed significant differences only in the ipsilateral and contralateral caudate. Our data indicate that in akinetic-rigid patients the dopaminergic system is more involved compared to that in the tremor type patients and that this difference is present from the initial stage of the disease. Moreover, our results suggest that PD phenotypes could be related not only to the dopaminergic involvement but also to other systems.

The clinical efficacy of L-DOPA and STN-DBS share a common marker: reduced GABA content in the motor thalamus.

At odd with traditional views, effective sub-thalamic nucleus (STN) deep brain stimulation (DBS), in Parkinson's disease (PD) patients, may increase the discharge rate of the substantia nigra pars reticulata and the internal globus pallidus (GPi), in combination with increased cyclic guanosine monophosphate (cGMP) levels. How these changes affect the basal ganglia (BG) output to the motor thalamus, the crucial structure conveying motor information to cortex, is critical. Here, we determined the extracellular GABA concentration in the ventral anterior nucleus (VA) during the first delivery of STN-DBS (n=10) or following levodopa (LD) (n=8). Both DBS and subdyskinetic LD reversibly reduced (-30%) VA GABA levels. A significant correlation occurred between clinical score and GABA concentration. By contrast, only STN-DBS increased GPi cGMP levels. Hence, STN-ON and MED-ON involve partially different action mechanisms but share a common target in the VA. These findings suggest that the standard BG circuitry, in PD, needs revision as relief from akinesia may take place, during DBS, even in absence of reduced GPi excitability. However, clinical amelioration requires fast change of thalamic GABA, confirming, in line with the old model, that VA is the core player in determining thalamo-cortical transmission.

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 the pedunculopontine tegmentum and subthalamic nucleus: effects on gait in Parkinson's disease.

OBJECTIVE: This study examines the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) and pedunculopontine tegmentum (PPTg) DBS in advanced Parkinson's disease using gait analysis. METHODS: Five people underwent bilateral DBS in both the STN and PPTg. Gait analysis was performed one year after neurosurgery using an optoelectronic system. The effects of DBS (STN, PPTg and STN+PPTg) were studied in two clinical conditions: without (Off) and during (On) antiparkinsonian therapy. RESULTS: PPTg and STN DBS were associated with changes in spatio-temporal and kinematics variables. CONCLUSIONS: Although experimental data cannot be generalized widely due to the small sample, PPTg DBS appears to affect the neuronal circuits subserving gait.

Deep brain stimulation of pedunculopontine tegmental nucleus (PPTg) promotes cognitive and metabolic changes: a target-specific effect or response to a low-frequency pattern of stimulation?

Deep brain stimulation (DBS) is a reliable treatment for advanced Parkinson's disease (PD) patients, but a possible risk of worsening cognitive functions, although modest, may postpone or halt DBS clinical indication. In a small cohort of PD patients we have pioneered the simultaneous implantation of both the subthalamic nucleus (STN) and the pedunculopontine tegmental nucleus (PPTg). Here we describe the cognitive test performance and the corresponding cortical metabolic activity, as assessed through 18-fluorodeoxyglucose (FDG)-positron emission tomography (PET), of these six PD patients tested in PPTg-ON vs- PPTg-OFF condition. PPTg-ON condition (at low frequency, 25 Hz) induced better performance in tests exploring both executive and attentive domains, which were coupled with an increased glucose utilization in prefrontal and frontal bilateral cortical areas, including both lateral (i.e., BA9) and more antero-medial cortices (BA 25-32). Moreover, during PPTg-ON, a surprising increase of FDG consumption was also observed in the left ventral striatum. These data are consistent with the hypothesis of a positive effect of 25 Hz PPTg-DBS on PD patients' cognitive profile, probably due to a facilitatory effect exerted by PPTg on both associative and limbic pathways.

Pathological gambling from dopamine agonist and deep brain stimulation of the nucleus tegmenti pedunculopontine.

In patients with Parkinson's disease, aberrant or excessive dopaminergic stimulation is commonly indicated as the trigger factor in unmasking impulse control disorders (ICDs) such as pathological gambling. We had the opportunity to follow a patient who experienced Parkinson's disease 7 years ago when he was using pramipexole and again, recently, when he was treated with levodopa (L-dopa) and low frequency stimulation of the nucleus of the pedunculopontine tegmentus (PPTg) but no dopamine agonists. The same patient had shown, when studied with fluorodeoxyglucose-positron emission tomography in the condition PPTg-ON, a peculiar increased activity in the left ventral striatum. This case report confirms that, in a predisposed personality, ICD may arise from the perturbation of endogenous pathways, which connect the brainstem to the basal ganglia.

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.

Helicobacter pylori eradication and l-dopa absorption in patients with PD and motor fluctuations.

OBJECTIVE: To investigate if Helicobacter pylori (HP) eradication could make an effective and long-lasting improvement in the pharmacokinetic and clinical response to l-dopa in patients with Parkinson disease (PD) and motor fluctuations. METHODS: In a group of 34 HP-infected, motor-fluctuating patients with PD, the short-term (1-week) and long-term (3-month) beneficial effect of HP eradication (n = 17) was investigated in a double-blind fashion in comparison with a generic antioxidant treatment (n = 17), by means of pharmacokinetic, clinical, and gastrointestinal assessments. Results were compared with placebo treatment. RESULTS: Differently from the antioxidant-treated patients, the HP-eradicated patients showed a significant increase of l-dopa absorption, which was coupled with a significant improvement of clinical disability and with a prolonged "on-time" duration, whereas gastritis/duodenitis scores significantly decreased in line with a better l-dopa pharmacokinetics. CONCLUSIONS: These data demonstrate a reversible Helicobacter pylori (HP)-induced interference with l-dopa clinical response related to the impaired drug absorption, probably due to active gastroduodenitis. Therefore, the authors suggest that HP eradication may improve the clinical status of infected patients with Parkinson disease and motor fluctuations by modifying l-dopa pharmacokinetics.

Effect of cabergoline added to levodopa treatment on sleep-wake cycle in idiopathic Parkinson's disease: an open label 24-hour polysomnographic study.

Few studies focused on the effects of cabergoline on sleep-wake cycle in PD. Twelve patients affected by PD treated with levodopa as monotherapy underwent two 24-hour ambulatory polysomnographic (A-PSG) sessions twice: in baseline condition (levodopa as monotherapy) and after addition of cabergoline. In each condition, a subjective evaluation of sleep quality and daytime sleepiness was obtained by means of Parkinson's disease Sleep Scale (PDSS) and the Epworth Sleepiness Scale. The statistical analysis of sleep parameters revealed a significant increase of sleep efficiency and slow wave sleep under cabergoline. The PDSS total score showed a significant improvement of overall sleep quality after cabergoline. No significant changes in daytime sleepiness were observed. No patient referred and/or showed sleep attacks before and after addition of cabergoline. We hypothesize that the long-lasting effect of cabergoline may improve the objective quality of nocturnal sleep in PD patients complaining nocturnal motor disability without inducing daytime sleepiness.

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.