The severity of corneal nerve loss differentiates motor subtypes in patients with Parkinson's disease.

Background: Parkinson's disease (PD) is a heterogeneous movement disorder with patients manifesting with either tremor-dominant (TD) or postural instability and gait disturbance (PIGD) motor subtypes. Small nerve fiber damage occurs in patients with PD and may predict motor progression, but it is not known whether it differs between patients with different motor subtypes. Objective: The aim of this study was to explore whether there was an association between the extent of corneal nerve loss and different motor subtypes. Methods: Patients with PD classified as TD, PIGD, or mixed subtype underwent detailed clinical and neurological evaluation and corneal confocal microscopy (CCM). Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) were compared between groups, and the association between corneal nerve fiber loss and motor subtypes was investigated. Results: Of the 73 patients studied, 29 (40%) had TD, 34 (46%) had PIGD, and 10 (14%) had a mixed subtype. CNFD (no./mm2, 24.09 ± 4.58 versus 28.66 ± 4.27; p < 0.001), CNBD (no./mm2, 28.22 ± 11.11 versus 37.37 ± 12.76; p = 0.015), and CNFL (mm/mm2, 13.11 ± 2.79 versus 16.17 ± 2.37; p < 0.001) were significantly lower in the PIGD group compared with the TD group. Multivariate logistic regression showed that higher CNFD (OR = 1.265, p = 0.019) and CNFL (OR = 1.7060, p = 0.003) were significantly associated with the TD motor subtype. The receiver operating characteristic (ROC) analysis demonstrated that combined corneal nerve metrics showed excellent discrimination between TD and PIGD, with an area under the curve (AUC) of 0.832. Conclusion: Greater corneal nerve loss occurs in patients with PIGD compared with TD, and patients with a higher CNFD or CNFL were more likely to have the TD subtype. CCM may have clinical utility in differentiating different motor subtypes in PD.

Corneal confocal microscopy differentiates patients with Parkinson's disease with and without autonomic involvement.

Autonomic dysregulation in Parkinson's disease (PD) can precede motor deficits and is associated with reduced quality of life, disease progression, and increased mortality. Objective markers of autonomic involvement in PD are limited. Corneal confocal microscopy (CCM) is a rapid ophthalmic technique that can quantify small nerve damage in a range of peripheral and autonomic neuropathies. Here we investigated whether CCM can be used to assess autonomic symptoms in PD. Based on the scale for outcomes in Parkinson's disease for autonomic symptoms (SCOPA-AUT), patients with PD were classified into those without autonomic symptoms (AutD-N), with single (AutD-S), and multiple (AutD-M) domain autonomic dysfunction. Corneal nerve fiber pathology was quantified using CCM, and the relationship with autonomic symptoms was explored. The study enrolled 71 PD patients and 30 control subjects. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and CNBD/CNFD ratio were lower in PD patients with autonomic symptoms compared to those without autonomic symptoms. Autonomic symptoms correlated positively with CNFD (r = -0.350, p = 0.004), and were not related to Levodopa equivalent daily dose (r = 0.042, p = 0.733) after adjusting for age, disease severity, disease duration or cognitive function. CCM parameters had high sensitivity and specificity in distinguishing patients with PD with and without autonomic symptoms. PD patients with autonomic symptoms have corneal nerve loss, and CCM could serve as an objective ophthalmic imaging technique to identify patients with PD and autonomic symptoms.

Corneal nerve fiber loss relates to cognitive impairment in patients with Parkinson's disease.

Cognitive impairment in Parkinson's disease (PD) adversely influences quality of life. There is currently no available biomarker to predict cognitive decline in PD. Corneal confocal microscopy (CCM) has been used as a non-invasive tool for quantifying small nerve damage in PD. The present study investigated whether corneal nerve measures were associated with cognitive function in PD. Patients with PD were classified into those with normal cognitive function (PD-CN), mild cognitive impairment (PD-MCI), and dementia (PDD). Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) were quantified with CCM and compared with a control group. Sixty-five PD patients and thirty controls were studied. CNFD was decreased and CNBD was increased in PD patients compared to controls (P < 0.05). CNBD and CNBD/CNFD ratio was higher in PD-CN compared to controls. CNFD was positively correlated with the Montreal cognitive assessment (MoCA) score (r = 0.683, P < 0.001), but negatively associated with unified Parkinson disease rating scale (UPDRS)-part III (r = -0.481, P < 0.001) and total UPDRS scores (r = -0.401, P = 0.001) in PD patients. There was no correlation between CNFD and Levodopa equivalent daily dose (LEDD) (r = 0.176, P = 0.161). CNFD, CNBD, CNFL, and CNBD/CNFD ratio was lower with increasing Hoehn and Yahr stage. PD patients show evidence of corneal nerve loss compared with controls and corneal nerve parameters are associated with the severity of cognitive and motor dysfunction in PD. CCM could serve as an objective in vivo ophthalmic imaging technique to assess neurodegeneration in PD.

[Effects of donepezil treatment on platelets α and ß secretase activities in Alzheimer's disease patients].

OBJECTIVE: To explore the effects of donepezil on the activities of platelet α and ß secretases in Alzheimer's disease (AD) patients. METHODS: During the period of 2007 - 2010, a total of 76 AD patients received either regular treatment alone or in combination with donepezil (5 mg/d) for a 12-week period. And their effects on ADAS-Cog (Alzheimer's disease assessment scale-cognitive subscale) total and ADL (activity of daily living) scores were measured. The effects of donepezil on α and ß secretase activities and sAPPα (soluble amyloid precursor protein α) secretion in AD patients and non-demented patients were detected by fluorescence and Western blot respectively. RESULTS: After the donepezil treatment, the ADAS-Cog scores of the treatment group decreased versus the control [(5.3 ± 4.4) vs (1.7 ± 1.6)]. And the differences were statistically significant (P < 0.01). And the ADL scores of the treatment group decreased versus the control [(41 ± 7) vs. (48 ± 6)]. And the differences were statistically significant (P < 0.05). As compared with that of pre-treatment (50 ± 6), the differences were statistically significant (P < 0.05). The activity of α secretase increased markedly while that of ß secretase decreased markedly versus the controls [(91% ± 9%) vs (64% ± 8%), P < 0.01; (119% ± 11%) vs (178% ± 17%), P < 0.01]. Both had significant statistical differences with those of pre-treatment (both P < 0.01). As compared with the non-demented group (100% ± 12%, P < 0.001), the sAPPα contents of treatment and control groups were (64% ± 14%, P < 0.01) and (26% ± 8%, P < 0.001) respectively. CONCLUSION: The administration of donepezil in AD patients improves cognitive functions and daily activities as indicated by the decreased ADAS-Cog total scores and ADL scores through the increased activity of α secretase and the decreased activity of ß secretase. The clinical efficacy of donepezil may be attributed to its pharmacological effects on the regulation of platelet secretase activities.

[Effect of estrogen-depletion and 17beta-estradiol replacement therapy upon rat hippocampus beta-amyloid generation].

OBJECTIVE: To observe the effects of estrogen depletion and 17beta-estradiol replacement therapy upon ratbeta-amyloid (Abeta) generation and the possible related mechanisms. METHODS: Rat ovaries were ectomized to mimic estrogen-depletion models and then 17beta-estradiol was administered by powdering hormone into soy-free chow as a way of replacement therapy. ELISA was carried out to detect rat hippocampus Abeta levels and alpha- and beta-secretase activities were measured after the experiment. The effects of estrogen depletion and 17beta-estradiol replacement therapy upon beta-secretase (BACE1) and neprilysin (NEP) expression were also analyzed by Western blot. RESULTS: Ovariectomy significantly decreased estrogen level [(11 + or - 4) pg/ml, P < 0.01] as compared with control group [(21 + or - 8) pg/ml] while 17beta-estradiol administration increased the estrogen level [(63 + or - 13) pg/ml, P < 0.01] in blood. The Abeta40 [(28.5 + or - 4.5) ng/ml, P < 0.01] and Abeta42 [(4.5 + or - 1.2) ng/ml, P < 0.01] levels were higher in ovariectomy group as compared with their respective control group [with Abeta40 (14.4 + or - 2.4) ng/ml and Abeta42 (2.8 + or - 0.4) ng/ml respectively]. But the effects of ovariectomy on Abeta content can be partially reversed by 17beta-estradiol replacement therapy [with Abeta40 (20.3 + or - 3.2)ng/ml, P < 0.01 and Abeta42 (3.8 + or - 0.5)ng/ml, P < 0.01 respectively]. Estrogen depletion decreased alpha-secretase activity (67.5%, P < 0.01) and increased beta-secretase activity (145.8%, P < 0.01) and this effect can be blocked by 17beta-estradiol administration [with alpha-secretase activity to 90.2% (P < 0.01) and beta-secretase activity to 92.4% (P < 0.01)]. Ovariectomy increased BACE1 expression (135.4%, P < 0.01) and decreased NEP expression (40.8%, P < 0.01) and this effect can be partially antagonized by 17beta-estradiol supplementary [with BACE to 103.5% (P < 0.01) and NEP to 88.4% (P < 0.01)]. CONCLUSION: Estrogen depletion can increase Abeta generation through the effects of increased beta-secretase activity and decreased alpha-secretase activity. Ovariectomy also increases BACE1 expression and decreases NEP expression. The 17beta-estradiol supplementary can decrease Abeta generation and this may to some extent explain why estrogen replacement therapy can decrease the risk of Alzheimer's disease in postmenopausal women.