Freezing of gait (FoG) is a unique and disabling clinical phenomenon characterised by brief episodes of inability to step or by extremely short steps that typically occur on initiating gait or on turning while walking. Patients with FoG, which is a feature of parkinsonian syndromes, show variability in gait metrics between FoG episodes and a substantial reduction in step length with frequent trembling of the legs during FoG episodes. Physiological, functional imaging, and clinical-pathological studies point to disturbances in frontal cortical regions, the basal ganglia, and the midbrain locomotor region as the probable origins of FoG. Medications, deep brain stimulation, and rehabilitation techniques can alleviate symptoms of FoG in some patients, but these treatments lack efficacy in patients with advanced FoG. A better understanding of the phenomenon is needed to aid the development of effective therapeutic strategies.

Freezing of gait: Moving forward on a mysterious clinical phenomenon

Cognitive impairment in patients with Parkinson's disease is gaining increased clinical significance owing to the relative success of therapeutic approaches to the motor symptoms of this disorder. Early investigations contributed to the concept of subcortical dementia associated with bradyphrenia and cognitive rigidity. For cognition in parkinsonian disorders, this notion developed into the concept of mild cognitive impairment and fronto-executive dysfunction in particular, driven mainly by dopaminergic dysmodulation and manifesting as deficits in flexibility, planning, working memory, and reinforcement learning. However, patients with Parkinson's disease could also develop a syndrome of dementia that might depend on non-dopaminergic, cholinergic cortical dysfunction. Recent findings, supplemented by advances in neuroimaging and genetic research, reveal substantial heterogeneity in the range of cognitive deficits in patients with Parkinson's disease. Remediation and management prospects for these cognitive deficits are based on neuropharmacological and cognitive rehabilitation approaches.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(10)70212-X.pdf

Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson's disease

Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are associated with severe cognitive decline, but it is still unclear to what extent they become functionally more similar over time. Methods: We compared amnestic mild cognitively impaired (aMCI; n = 29) patients to mild cognitively impaired (MCI) PD patients (n = 25), and patients with AD (n = 34) to patients with PD dementia (PDD; n = 15) with respect to cognitive functioning and mood. Results: aMCI patients were impaired in episodic memory, while MCI PD patients showed deficits in visuoconstruction and attention. AD and PDD patients showed comparable deficits on tests for language, attention and visuoconstruction. However, unlike PDD patients but similar to aMCI patients, AD patients showed a characteristic memory impairment, especially commission errors on recognition tasks, whereas PDD patients scored higher on the depressive mood questionnaire. Conclusions: In advanced stages of both diseases, the pattern of functional deficits associated with parietal and temporal lobe functions (attention, visuoconstruction and language) is similar. However, specific differences, already present in the early stage (recognition errors in AD, associated with mediobasal temporal lobe functioning, and depressed mood in PDD, associated with non-motor basal ganglia loops), are also observed in the late stage.

/pdf/cognitive-profiles-of-patients-with-mild-cognitive-48403gz1n2.pdf

Cognitive Profiles of Patients with Mild Cognitive Impairment or Dementia in Alzheimer's or Parkinson's Disease

Unified Parkinson's Disease Rating Scale

https://www.medicinalgenomics.com/wp-content/uploads/2011/12/Mitochondria_Ox-Stress_Neurology.pdf

Mitochondria, oxidative stress and neurodegeneration.

Freezing of gait (FOG) is a frequent, disabling symptom of Parkinson's disease (PD). FOG usually lasts a few seconds. It refers to brief paroxysmal events during which a subject is unable to start or continue locomotion. Despite its frequency, FOG pathophysiology is unclear. Because a frontal lobe dysfunction or a disconnection between the frontal lobe and basal ganglia has been implicated in FOG, we explored frontal functions in PD patients using neuropsychological tests. Thirteen early-stage PD patients [Hoehn & Yahr score (HY phonemic verbal fluency: P = 0.011; TPCT: P = 0.024). FOG correlated with lower scores at frontal tests in patients with early-stage PD.

Freezing of gait and executive functions in patients with Parkinson's disease.

Visual hallucinations (VHs) represent a frequent and disturbing complication of Parkinson's disease. Evidence suggests that VH can be related to central cholinergic dysfunction. Short-latency afferent inhibition (SAI) technique gives the opportunity to test an inhibitory cholinergic circuit in the human cerebral motor cortex. This inhibition of motor-evoked potentials can be observed when transcranial magnetic stimulation is delivered with a delay ranging from 2 to 8 ms, after a peripheral nerve afferent input has reached the somatosensory cortex. We applied SAI technique in 10 non-demented patients with Parkinson's disease with VHs, in 12 non-demented patients with Parkinson's disease without VHs (NVH-pts) and in 11 age-matched normal controls. All patients with Parkinson's disease underwent a battery of neuropsychological tests to assess frontal and visuospatial functions, memory and attention. SAI was significantly reduced in patients with VHs compared with controls and patients without VHs. Neuropsychological examination showed a mild cognitive impairment in 16 out of 22 patients with Parkinson's disease. In addition, we found that in our patients with VHs, performance of some tasks evaluating visuospatial functions and attentional/frontal lobe functions was significantly more impaired than in patients without VHs. SAI abnormalities, presence of VH and neuropsychological results strongly support the hypothesis of cholinergic dysfunction in some patients with Parkinson's disease, who will probably develop a dementia. A follow-up study of our patients is required to verify whether SAI abnormalities can predict a future severe cognitive decline. Moreover, SAI can also be very useful to follow-up the efficacy of anti-cholinesterase therapies.

Functional involvement of central cholinergic circuits and visual hallucinations in Parkinson's disease

Objective: The number of patients in prolonged postanoxic vegetative state (VS) is increasing. However, little information is available about prognostic markers of long-term outcome in patients who remain in VS more than 1 month postonset. The present 2-year prospective clinical study aimed to identify prognostic markers, recorded in the chronic phase, that might be useful for predicting recovery of responsiveness in a cohort of postanoxic VS patients. Methods: We enrolled 43 inpatients with prolonged anoxic VS (23 female; age range 12–83 years). We collected data about medical history, clinical findings, and neurophysiological assessments at study entry (1–6 months postonset), and assessed their relationships with outcome at 24 months postonset; for defining outcome, patients were classified as responsive or unresponsive on the basis of clinical criteria and on Coma Recovery Scale–Revised (CRS-R). Results: Nine patients had recovered responsiveness (but 2 of them died after awakening), whereas 12 patients remained in VS and 22 had died in VS. Functional abilities were severely affected in all responsive survivors. Responsive patients were significantly younger and showed higher CRS-R total score and lower Disability Rating Scale score at study entry than patients who did not recover. All responsive survivors had spared pupillary light reflex and nociceptive response, and paroxysmal sympathetic hyperactivity. Logistic regression analysis showed that the presence of median nerve somatosensory evoked potentials and CRS-R total score ≥6 were significant predictors of recovery of responsiveness. Conclusions: Clinical features and evoked potentials are useful predictors of long-term recovery of responsiveness in patients with prolonged postanoxic VS.

Predictors of recovery of responsiveness in prolonged anoxic vegetative state

Background Non-motor symptoms are very common among patients with Parkinson9s disease since the earliest stage, but little is known about their progression and their relationship with dopaminergic replacement therapy. Methods We studied non-motor symptoms before and after 2 years from dopaminergic therapy introduction in ninety-one newly diagnosed previously untreated PD patients. Results At baseline, nearly all patients (97.8%) referred at least one non-motor symptom. At follow-up, only few non-motor symptoms significantly changed. Particularly, depression and concentration became less frequent, while weight change significantly increased after introduction of dopamine agonists. Conclusions We reported for the first time a 2-year prospective study on non-motor symptoms before and after starting therapy in newly diagnosed PD patients. Even if non-motor symptoms are very frequent in early stage, they tend to remain stable during the early phase of disease, being only few non-motor symptoms affected from dopaminergic therapy and, specifically, by the use of dopamine agonists.

https://jnnp.bmj.com/content/jnnp/early/2012/09/18/jnnp-2012-303419.full.pdf

Non-motor symptoms in early Parkinson's disease: a 2-year follow-up study on previously untreated patients

To explore the relationship between depression and cognitive impairment in non-demented PD patients, we evaluated neurological and neuropsychological asset in 65 patients with a diagnosis of major depressive disorder (dPD) according to DSM-IV criteria and 60 patients without depression (nPD). Compared with nPD patients, dPD patients had significantly higher scores on behavioral rating scales and performed worse on the Frontal Assessment Battery (FAB), Semantic Fluency Task, Copying Task (CT), and Stroop Test. Three dPD subgroups were identified based on the first two DSM-IV criteria: patients fulfilling criterion 1 (depressed mood; group 1); patients fulfilling criterion 2 (apathy/anhedonia; group 2); patients fulfilling criteria 1 and 2 (group 3). Patients of group 2 scored significantly lower than patients of group 1 on the CT, FAB and phonological fluency task. Patients of groups 2 and 3 scored significantly lower than nPD patients on visuoconstructional and frontal tasks. Similar results were obtained in dPD patients stratified in four subgroups based on cut-off scores of the Apathy Evaluation Scale and the Snaith Hamilton Pleasure Scale. In summary, PD patients with concomitant apathy and anhedonia may show more severe cognitive impairments. Since such patients are diagnosed to be affected by depression according to clinical DSM-IV criteria, we suggest that DSM-IV criteria may not distinguish an affective from a cognitive disorder in PD.

Autilia Cozzolino

Papers

Freezing of gait and executive functions in patients with Parkinson's disease.

Functional involvement of central cholinergic circuits and visual hallucinations in Parkinson's disease

Predictors of recovery of responsiveness in prolonged anoxic vegetative state

Non-motor symptoms in early Parkinson's disease: a 2-year follow-up study on previously untreated patients

Relationship between depression and cognitive dysfunctions in Parkinson’s disease without dementia