Cerebral hemodynamics and cognitive functions in the acute and subacute stage of mild ischemic stroke: a longitudinal pilot study.

The association between cerebral hemodynamics and cognitive impairment has been reported in neurodegenerative and cerebrovascular disorders (CVD). However, it is still unclear whether changes occur in the acute phase of CVD. Here we investigated cognitive and hemodynamic parameters and their association in patients with CVD during the acute and subacute phases. Seventy-three patients with mild stroke, not undergoing endovascular treatment, were recruited. All subjects were devoid of intracranial or external carotid stenosis, significant chronic cerebrovascular pathology, dementia or non-compensated cardiovascular diseases. Patients were evaluated within 7 days from symptoms onset (T1) and after 3 months (T2). Clinical and demographic data were collected. NIHSS, MoCA, FAB, and Word-Color Stroop test (WCST) were used to evaluate disease severity and cognitive functions. Basal hemodynamic parameters in the middle cerebral artery were measured with transcranial Doppler. Differences between T2 and T1, correlations between cognitive and hemodynamic variables at T1 and T2, as well as correlations between the T2-T1 variation in cognitive and hemodynamic parameters were assessed. At T1, cognitive performance of MoCA, FAB, and WCST was lower compared with T2; and pulsatility index, a parameter reflecting distal vascular resistance, was higher. However, no correlations between the changes in cognitive and hemodynamic variables were found; therefore, the two seems to be independent phenomena. In the acute phase, the linear association between cerebral blood flow and cognitive performances was lost, probably due to a differential effect of microenvironment changes and vascular-specific phenomena on cognition and cerebral hemodynamics. This relationship was partially restored in the subacute phase.

Monoamine-oxidase Type B Inhibitors and Cognitive Functions in Parkinson's Disease: Beyond the Primary Mechanism of Action.

Symptoms of cognitive impairment are rather common since the early stage of Parkinson's disease (PD); they aggravate with disease progression and may lead to dementia in a significant proportion of cases. Worsening of cognitive symptoms in PD patients depends on the progression of subcortical dopaminergic damage as well as the involvement of other brain neurotransmitter systems in cortical and subcortical regions. Beyond the negative impact on disability and quality of life, the presence and severity of cognitive symptoms may limit adjustments of dopamine replacement therapy along the disease course. This review focuses on the consequences of the administration of monoamine-oxidase type Binhibitors (MAOB-I) on cognition in PD patients. Two drugs (selegiline and rasagiline) are available for the treatment of motor symptoms of PD as monotherapy or in combination with L-DOPA or dopamine agonists in stable and fluctuating patients; a further drug (safinamide) is usable in fluctuating subjects solely. The results of available studies indicate differential effects according to disease stage and drug features. In early, non-fluctuating patients, selegiline and rasagiline ameliorated prefrontal executive functions, similarly to other dopaminergic drugs. Benefit on some executive functions was maintained in more advanced, fluctuating patients, despite the tendency of worsening prefrontal inhibitory control activity. Interestingly, high-dose safinamide improved inhibitory control in fluctuating patients. The benefit of high-dose safinamide on prefrontal inhibitory control mechanisms may stem from its dual mechanism of action, allowing reduction of excessive glutamatergic transmission, in turn secondary to increased cortical dopaminergic input.

The impact of cerebral vasomotor reactivity on cerebrovascular diseases and cognitive impairment.

The regulation of cerebral blood flow (CBF) is a complex and tightly controlled function ensuring delivery of oxygen and nutrients and removal of metabolic wastes from brain tissue. Cerebral vasoreactivity (CVR) refers to the ability of the nervous system to regulate CBF according to metabolic demands or changes in the microenvironment. This can be assessed through a variety of nuclear medicine and imaging techniques and protocols. Several studies have investigated the association of CVR with physiological and pathological conditions, with particular reference to the relationship with cognitive impairment and cerebrovascular disorders (CVD). A better understanding of the interaction between CVR and cognitive dysfunction in chronic and particularly acute CVD could help improving treatment and rehabilitation strategies in these patients. In this paper, we reviewed current knowledge on CVR alterations in the context of acute and chronic CVD and cognitive dysfunction. Alterations in CVR and hemodynamics have been described in patients with both neurodegenerative and vascular cognitive impairment, and the severity of these alterations seems to correlate with CVR derailment. Furthermore, an increased risk of cognitive impairment progression has been associated with alterations in CVR parameters and hemodynamics. Few studies have investigated these associations in acute cerebrovascular disorders and the results are inconsistent; thus, further research on this topic is encouraged.

Switch from rasagiline to safinamide in fluctuating Parkinson's disease patients: a retrospective, pilot study.

Besides the inhibition of monoamine-oxidase-B, high-dose safinamide (100 mg) also blocks voltage-gated Na+ and Ca++ channels and inhibits glutamate release at overactive synapses. This latter mechanism may provide further benefit to fluctuating Parkinson's disease (PD) patients compared to rasagiline. Here, we retrospectively investigated the consequences of shifting from rasagiline to high-dose safinamide in PD patients reporting symptoms of wearing-off, defined by the Wearing-Off-Questionnaire-19 (WOQ-19) score ≥3 at baseline. Seventeen PD patients were switched from rasagiline 1 mg to safinamide 100 mg because of the report of symptoms of fluctuations while under therapy with either levodopa+rasagiline or levodopa+rasagiline+dopamine agonists, or re-occurrence of fluctuations previously corrected by add-on with rasagiline. Patients were re-evaluated 4-6 months after switch. Switch to safinamide 100 mg produced benefit in 9/17 (52.9%) subjects, together with significant reduction of subjective symptoms of wearing-off. There was no report of adverse events. Findings from this retrospective, exploratory study suggest that safinamide 100 mg may produce more powerful benefit that rasagiline 1 mg as add-on to levodopa in fluctuating PD patients, possibly because of the bimodal mechanism of action of the former drug.

Safinamide improves executive functions in fluctuating Parkinson's disease patients: an exploratory study.

Safinamide is a monoamine-oxidase-B inhibitor with peculiar features. At the dose of 100 mg/day, safinamide stimulates dopaminergic transmission and reduces glutamatergic transmission. Here, we investigated the effects of safinamide 100 mg on executive functions at the end of levodopa dose in fluctuating Parkinson's disease (PD) patients. Thirty-two fluctuating PD patients were submitted at baseline (V1) to the UPDRS-III, the Frontal Assessment Battery (FAB) and the Stroop-Word-Color-Test (SWCT) at the end of levodopa dose. Safinamide was then added to the original therapy. After 12 weeks of treatment, patients underwent the final visit (V2), including the UPDRS-III, the FAB and the SWCT with the same daily time schedule as V1. Treatment with safinamide was associated with significant increases of the total FAB score, SWCT-interference time score and UPDRS-III score. Within FAB subdomains, add-on with safinamide significantly increased motor programming and increased mental flexibility and inhibitory control scores. The results of this exploratory study show that add-on with safinamide improves executive functions at the end of levodopa dose in fluctuating PD patients. In particular, attention and inhibition of cognitive interference were significantly ameliorated by add-on with safinamide, suggesting increased modulatory performances of prefrontal cortical pathways. If confirmed by future research on larger cohorts and under controlled conditions, the present results may represent the basis for a novel indication for the use of safinamide in fluctuating PD patients.

The tolerability, safety and efficacy of safinamide in elderly Parkinson's disease patients: a retrospective study.

Safinamide (SF) is a third-generation monoamine-oxidase-B inhibitor that proved efficacy as add-on to levodopa in fluctuating Parkinson's disease (PD) patients. Despite the high prevalence of complicated PD in older population, the data on the tolerability, safety and efficacy of SF in elderly patients are rather poor. Here we studied retrospectively the consequences of add-on with SF in PD patients older than 65 years. Fifty-three fluctuating PD patients were included (30 subjects aged between 65 and 75 years, the remaining 23 subjects aged > 75 years). Patients were treated with either 50 (n = 27) or 100 mg (n = 26) SF for at least 6 months. In all patients, fluctuations were identified by the report of a Wearing-Off-Questionnaire-19 (WOQ-19) score ≥ 3 at baseline. Add-on with SF was well tolerated and safe. Adverse events occurred in 30% of patients and led to drug discontinuation in 11% of cases. At follow-up visits, 60% of patients reported lowering of the WOQ-19 score to ≤ 2. There were no significant differences related to age or daily drug dose in tolerability, safety or efficacy. The results of this study provide evidence of the efficacy, tolerability and safety of SF in elderly PD patients.

Orthostatic hypotension acutely impairs executive functions in Parkinson's disease.

Orthostatic hypotension is a frequent non-motor symptom of Parkinson's disease, with negative prognostic role on cognitive functions. Here we measured the acute effects of orthostatic hypotension on executive functions in Parkinson's disease patients devoid of hypertension, carotid artery stenosis, and significant chronic cerebrovascular pathology. Measurements were carried out during regular visits in outpatient setting. Twenty-eight Parkinson's disease patients were recruited and studied along scheduled outpatient visits. They were divided into two groups (n = 14 each) based on the presence or lack of orthostatic hypotension. This was diagnosed according to international guidelines. All patients were submitted to the Stroop's test and to the phonological and semantic verbal fluency test after 10-min resting in supine position and immediately upon standing in upright position. Testing lasted less than 5 min in either position. In upright position, subjects with orthostatic hypotension displayed significantly worse performances at the Stroop's test word reading time (22.1 ± 4.1 vs. 14.9 ± 4.0 s), interference time (56.1 ± 12.3 vs. 41.4 ± 11.8 s), and number of errors at the interference section (5.8 ± 3.2 vs. 1.3 ± 2.1) as compared to those without orthostatic hypotension. These results demonstrate that worsening of attentive function upon standing can be measured in Parkinson's disease patients with orthostatic hypotension during routine outpatient visits. These findings suggest that clinically asymptomatic orthostatic hypotension in Parkinson's disease patients may acutely worsen neuropsychological performances with possible negative impact on daily functioning.

Rasagiline for dysexecutive symptoms during wearing-off in Parkinson's disease: a pilot study.

Wearing-off refers to the predictable worsening of motor and sometimes non-motor symptoms of Parkinson's disease occurring at the end of levodopa dose that improves with the next drug dose. Here, we investigated the efficacy of rasagiline on executive functions at the end of levodopa dose in patients displaying symptoms of wearing-off. Rasagiline was well-tolerated and produced a significant improvement at the Frontal Assessment Battery, together with improvement of motor symptoms at the end of levodopa dose. These results suggest that treatment of motor symptoms of wearing-off with rasagiline may be accompanied by improvement of executive functions, and further support the need for optimizing dopamine replacement therapy in fluctuating Parkinson's disease patients.