The efficacy of deep brain stimulation (DBS) for Parkinson disease (PD) is well established for up to 1 or 2 years, but long-term outcome data are still limited. In this Review, we critically discuss the evidence on the long-term outcomes of DBS and consider the clinical implications. Although many patients are lost to follow-up, the evidence indicates that subthalamic nucleus DBS improves motor function for up to 10 years, although the magnitude of improvement tends to decline over time. Functional scores recorded during on-medication periods worsen more quickly than those recorded in off periods, consistent with the degeneration of non-dopaminergic pathways. Dyskinesia, motor fluctuations and activities of daily living in off periods remain improved at 5 years, but quality-of-life scores have usually fallen below preoperative levels. The incidence and severity of dementia among patients receiving DBS are comparable to those among patients who receive medical treatment. Severe adverse events are rare, but adverse events such as dysarthria are common and probably under-reported. Long-term data on the outcomes of globus pallidus interna DBS are limited and mostly confirm the efficacy for dyskinesia. A trend towards offering DBS in the earlier stages of PD creates a need to identify factors that predict long-term outcomes and to discuss realistic expectations with patients preoperatively.

/pdf/long-term-outcomes-of-deep-brain-stimulation-in-parkinson-5gjwef1917.pdf

Long-term outcomes of deep brain stimulation in Parkinson disease

Since the discovery of CSF1R gene mutations in families with hereditary diffuse leukoencephalopathy with spheroids in 2012, more than 70 different mutations have been identified around the world. Through the analyses of mutation carriers, CSF1R-related leukoencephalopathy has been distinctly characterized clinically, radiologically, and pathologically. Typically, patients present with frontotemporal dementia-like phenotype in their 40s–50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs. Women tend to develop the clinical symptoms at a younger age than men. On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks. Primary axonopathy followed by demyelination was suggested by pathology. Haploinsufficiency of colony-stimulating factor-1 receptor (CSF1R) is evident in a patient with a frameshift mutation, facilitating the establishment of Csf1r haploinsufficient mouse model. These mice develop clinical, radiologic, and pathologic phenotypes consistent with those of human patients with CSF1R mutations. In vitro, perturbation of CSF1R signaling is shown in cultured cells expressing mutant CSF1R. However, the underlying mechanisms by which CSF1R mutations selectively lead to white matter degeneration remains to be elucidated. Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies, of which microglia have a pivotal and primary role in pathogenesis. In this review, we address the current knowledge of CSF1R-related leukoencephalopathy and discuss the putative pathophysiology, with a focus on microglia, as well as future research directions.

/pdf/csf1r-related-leukoencephalopathy-a-major-player-in-primary-dkcs1ee2is.pdf

CSF1R-related leukoencephalopathy: A major player in primary microgliopathies

Conversion to MCI and dementia in Parkinson's disease: a systematic review and meta-analysis

Objective:
Alzheimer’s disease and vascular dementia are responsible for more than 80% of dementia cases. These two conditions share common risk factors including hypertension. Cerebral small vessel disease (CSVD) is strongly associated with both hypertension and cognitive impairment. In this review, we identify the pathophysiological changes in CSVD that are caused by hypertension and further explore the relationship between CSVD and cognitive impairment.


Data Sources:
We searched and scanned the PubMed database for recently published literatures up to December 2017. We used the keywords of "hypertension" , "cerebral small vessel disease" , "white matter lesions" , "enlarged perivascular spaces" , "lacunar infarcts" , "cerebral microbleeds" , and "cognitive impairment" in the database of PubMed.


Study Selection:
Articles were obtained and reviewed to analyze the hypertension-induced pathophysiological changes that occur in CSVD and the correlation between CSVD and cognitive impairment.


Results:
In recent years, studies have demonstrated that hypertension-related changes (e.g., small vascular lesions, inflammatory reactions, hypoperfusion, oxidative stress, damage to autoregulatory processes and the blood-brain barrier, and cerebral amyloid angiopathy) can occur over time in cerebral small vessels, potentially leading to lower cognitive function when blood pressure (BP) control is poor or lacking. Both isolated and co-occurrent CSVD can lead to cognitive deterioration, and this effect may be attributable to a dysfunction in either the cholinergic system or the functionality of cortical and subcortical tracts.


Conclusions:
We explore the currently available evidence about the hypertensive vasculopathy and inflammatory changes that occur in CSVD. Both are vital prognostic indicators of the development of cognitive impairment. Future studies should be performed to validate the relationship between BP levels and CSVD progression and between the numbers, volumes, and anatomical locations of CSVD and cognitive impairment.


Key words: 
Cerebral Microbleeds; Cerebral Small Vessel Disease; Cognitive Impairment; Hypertension

Hypertension-Induced Cerebral Small Vessel Disease Leading to Cognitive Impairment

Granulocyte-colony stimulating factor (G-CSF) is a growth factor that has originally been identified several decades ago as a hematopoietic factor required mainly for the generation of neutrophilic granulocytes, and is in clinical use for that. More recently, it has been discovered that G-CSF also plays a role in the brain as a growth factor for neurons and neural stem cells, and as a factor involved in the plasticity of the vasculature. We review and discuss these dual properties in view of the neuroregenerative potential of this growth factor.

/pdf/the-granulocyte-colony-stimulating-factor-has-a-dual-role-in-2bqzi90lk7.pdf

The Granulocyte-colony stimulating factor has a dual role in neuronal and vascular plasticity.

Educational attainment and motor burden in advanced Parkinson's disease – The emerging role of education in motor reserve

The impact of white matter lesions on the cognitive outcome of subthalamic nucleus deep brain stimulation in Parkinson’s disease

Intraoperative test stimulation is established to optimize target localization in STN DBS, but requires a time-consuming awake surgery in off-medication state. The aim of this study was to compare the thresholds of stimulation-induced effects of test stimulation and the permanent electrode. Fifty-nine PD patients receiving bilateral STN DBS were clinically examined with stepwise increasing monopolar stimulation during surgery and DBS programming at matched stimulation depths. Thresholds of therapeutic and side effects were obtained from standardized examination protocols. Postoperative stimulation via the permanent electrode caused side effects at a significantly lower threshold than predicted during intraoperative test stimulation (P < 0.001); whereas sufficient therapeutic effects were achieved at significantly higher thresholds (P < 0.001). Intraoperative testing may lead to an overestimation of the therapeutic window. The two different electrodes lead to distinct spreading of the electric field in the STN and surrounding tissues that causes different volume of tissue activated (VTA). Clinicians involved in DBS surgery and programming should be aware of the differences in both stimulation settings, concerning electrodes geometry, stimulation modes as well as the impact of time. Therapeutic and side effects of permanent stimulation are not predictable by intraoperative test stimulation. Test stimulation may be an orientating test for very low thresholds of side effects instead.

Intraoperative clinical testing overestimates the therapeutic window of the permanent DBS electrode in the subthalamic nucleus

Early motor symptoms of neurodegenerative diseases often appear in combination with psychiatric symptoms, such as depression or personality changes, and are in danger of being misdiagnosed as psychogenic in young patients. We present the case of a 32-year-old woman who presented with rapid-onset depression, followed by a hypokinetic movement disorder and cognitive decline during pregnancy. Genetic testing revealed a mutation in the colony-stimulating factor 1 receptor gene, which led to the diagnosis of hereditary diffuse leukoencephalopathy with spheroids. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is probably an under-recognized disease. HDLS should be considered in patients with rapidly progressing parkinsonian symptoms and dementia accompanied by white matter lesions.

Josefine Blume

Papers

Educational attainment and motor burden in advanced Parkinson's disease – The emerging role of education in motor reserve

The impact of white matter lesions on the cognitive outcome of subthalamic nucleus deep brain stimulation in Parkinson’s disease

Intraoperative clinical testing overestimates the therapeutic window of the permanent DBS electrode in the subthalamic nucleus

Suspected Perinatal Depression Revealed to be Hereditary Diffuse Leukoencephalopathy with Spheroids.

Can intraoperative clinical testing predict stimulation-induced effects of STN-DBS?