The Mini-Cog, Clock Drawing Test, and the Mini-Mental State Examination in a German memory clinic: specificity of separation dementia from depression.

BACKGROUND: The aim of this study was to assess the specificities of the Mini-Cog, the Clock Drawing Test (CDT), and the Mini-Mental State Examination (MMSE) against depression and healthy controls in a German Memory Clinic. Furthermore, we analyzed the specificities of all three screening instruments in dependence of actual depression severity. METHODS: Data from 142 depressed elderly, 438 dementia patients, and 64 healthy controls were retrospectively analyzed. The CDT and an extraction of the three-item recall of the MMSE were used to constitute the Mini-Cog algorithm. Depression severity was rated by either the Beck Depression Inventory (BDI) or the Geriatric Depression Scale (GDS) depending on the age of the patients. RESULTS: The Mini-Cog achieved a specificity of 79.6% against depressed elderly and 100.0% against healthy subjects (p < 0.001). Similarly, the specificities of the CDT (83.8%) and MMSE (92.3% at a cut-off ≤24 and 90.8% at ≤25, respectively) against healthy subjects were significantly higher than the specificities against depressed patients (each p < 0.05). Concerning the depressed patients, the MMSE demonstrated significant higher specificity than the Mini-Cog and the CDT, but also showed the lowest sensitivity for the detection of dementia. Surprisingly, the depression severity had no effect on the specificity of the Mini-Cog and the CDT, only the MMSE was susceptible for the depression severity. CONCLUSION: Although the MMSE showed higher specificities, the weighting between the sensitivities and specificities in all tests prove again the Mini-Cog as a short, valid, and sensitive screening tool.

The Mini-Cog versus the Mini-Mental State Examination and the Clock Drawing Test in daily clinical practice: screening value in a German Memory Clinic.

BACKGROUND: The aim of this study was to compare the screening value of the Mini-Cog, Clock Drawing Test (CDT), Mini-Mental State Examination (MMSE) and the algorithm MMSE and/or CDT to separate elderly people with dementia from healthy depending on test time, type and severity of dementia, and demographic variables in a German Memory Clinic. METHODS: Data from a heterogeneous patient sample and healthy participants (n = 502) were retrospectively analyzed. Of the 438 patients with dementia, 49.1% of the dementia diagnoses were Alzheimer's dementia and 50.9% were non-Alzheimer's dementia. Sixty-four participants were classified as cognitively unimpaired. The CDT and an extraction of the 3-item recall of the MMSE were used to constitute the Mini-Cog algorithm. RESULTS: Overall, the Mini-Cog showed significantly higher discriminatory power (86.8%) than the MMSE (72.6% at a cut-off ≤ 24 and 79.2% at ≤ 25, respectively) and CDT (78.1%) (each p < 0.01) and did not perform worse than the algorithm MMSE and/or CDT (each p > 0.05). The specificity of the Mini-Cog (100.0%) was similar to that of the MMSE (100.0% for both cut-offs) and CDT (96.9%) (p = 0.154). For all age and educational groups the Mini-Cog outmatched the CDT and MMSE, and was less affected by education than MMSE and less susceptible for the dementia stage than the CDT. CONCLUSION: The Mini-Cog proved to have superior discriminatory power than either CDT or MMSE and is demonstrated to be a valid "short" screening instrument taking 3 to 4 minutes to administer in the geriatric setting.

Higher BDNF serum levels predict slower cognitive decline in Alzheimer's disease patients.

The neurotrophin brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal survival, synaptic plasticity, and memory. Several recent studies have demonstrated altered BDNF serum levels in Alzheimer's disease (AD) patients. However, the association of BDNF serum levels with the rate of cognitive decline in AD patients is still unclear. We demonstrate that BDNF serum levels are significantly decreased in AD patients with fast cognitive decline [decrease of Mini-Mental State Examination (MMSE) score >4/yr; n=12] compared to AD patients with slow cognitive decline (decrease of MMSE score ≤4/yr, n=28) and show a significant correlation with the rate of cognitive decline during 1 yr follow-up. These results suggest that higher BDNF serum levels are associated with a slower rate of cognitive decline in AD patients. Further longitudinal studies are necessary to elucidate the kinetics and the potential role of serum BDNF as a surrogate marker of disease progression in AD patients.

Exercise-induced normalization of decreased BDNF serum concentration in elderly women with remitted major depression.

Major depression (MD) has been associated with decreased brain-derived neurotrophic factor (BDNF) serum levels, while antidepressant drugs were found to increase these decreased BDNF levels. We investigated if this is also caused by a single exercise session in elderly women with remitted MD. In our study 35 elderly women with a (partially) remitted depressive episode of unipolar depression according to DSM-IV criteria within the last year and 20 age-matched healthy female controls were included. Depression severity was assessed by HAMD. Serum levels of BDNF were measured by ELISA. Blood samples were taken during the rest period before beginning the exercise including spiroergometry, at the end of the exercise and after a 30-min recovery period. At baseline MD patients showed significantly decreased BDNF serum levels compared to healthy female controls. After a single 30-min exercise period, we found a significant increase of BDNF serum levels in MD patients towards values comparable with the baseline levels of the healthy controls, followed by a significant decrease after 30 min rest, while the healthy controls showed only a mild but non-significant increase. In conclusion, a single exercise session leads to a significant up-regulation and transient normalization of BDNF serum levels in elderly women with remitted MD. This mechanism may contribute to the beneficial therapeutic and relapse-preventing effects of physical activity on MD.

Regulation of GDNF and its receptor components GFR-alpha1, -alpha2 and Ret during development and in the mature retino-collicular pathway.

The development of the retino-tectal projection as part of the central visual pathway is accomplished around postnatal day (P) 10-14 in rodents, and trophic factors are important for topographic refinement of this projection. Emerging data indicate that GDNF may influence synaptic plasticity of this projection. To date, maturation-dependent kinetics of GDNF release and expression and biological function of single GDNF receptors along the retino-collicular pathway are ill-defined. Here, we examined mRNA and protein expression of GDNF and its multicomponent receptor complex in the retina and superior colliculus (SC) during postnatal development of the rat visual system, and after optic nerve (ON) injury by RT-PCR, immunoblotting and immunofluorescence. Stable mRNA transcription of GDNF and its receptors GFR-alpha1, -alpha2 and Ret was found in retina and SC throughout development into adulthood and after ON transection. Expression of GDNF protein increased during retinal development, declined in adulthood and was further reduced in injured retina. In the SC, GDNF peaked at P0, continuously declined with maturation, and was undetectable in the deafferentiated SC. GFR-alpha1 was abundant in retina and SC throughout, while GFR-alpha2 was not expressed. Since Ret was localized primarily to the vascular compartment, the receptor tyrosine kinase may play a minor role in neuronal GDNF signaling. In summary, we provide evidence for GDNF as survival and guidance factor during development of the retino-tectal projection with differential regulation in early and premature retina and SC. Postlesionally, midbrain targets do not induce GDNF, suggesting that retrograde GDNF is not essential for rescue of adult injured retinal ganglion cells (RGCs).

Influence of lithium treatment on GDNF serum and CSF concentrations in patients with early Alzheimer's disease.

Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer's disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r = -0.585, p = 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r = - 0.755, p = 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p = 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p = 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.

Amyloid-ß peptides in plasma and cognitive decline after 1 year follow-up in Alzheimer's disease patients.

Plasma levels of amyloid-ß (Aß) peptides are potential biomarkers of early cognitive impairment and of Alzheimer's disease (AD) risk. However, the association of Aß peptides with the rate of cognitive decline in AD patients is still unclear. In the present study we demonstrate that Aß1₋42 plasma levels show a significant correlation with the rate of cognitive decline and are significantly increased in AD patients with fast cognitive decline (decrease of Mini-Mental Status Examination (MMSE) score ≥ 5/year; n = 12) compared to AD patients with slow cognitive decline (decrease of MMSE score ≤ 4/year; n = 28), independent of baseline MMSE scores, age and cholinesterase inhibitor intake, but dependent on history of myocardial infarction and history of stroke in a multivariate analysis. These results suggest that Aß1₋42 plasma levels are associated with the rate of cognitive decline in AD patients and may be influenced by atherosclerotic vasculopathies such as stroke and myocardial infarction.

Increased circulating progenitor cells in Alzheimer's disease patients with moderate to severe dementia: evidence for vascular repair and tissue regeneration?

Cerebrovascular dysfunction is a common finding in patients with Alzheimer's disease (AD) and may contribute to cognitive decline. Abundant evidence suggests that vascular and neuronal repair mechanisms are mediated by circulating progenitor cells in vivo. Whether CD34+ and, specifically, CD34+/CD133+ progenitor cells are involved in the pathophysiology of AD is poorly understood so far. In the present study, peripheral blood concentrations of circulating CD34+/CD133+ and CD34+ progenitor cells were measured in 45 AD patients and in 30 healthy elderly controls by flow cytometry. The severity of dementia was assessed by Mini-Mental Status Examination and Clinical Dementia Rating scale. AD patients were stratified into two groups showing mild (n=17) and moderate to severe (n= 28) dementia. In the present study, AD patients with moderate to severe dementia, but not those with mild dementia, showed significantly increased circulating CD34+/CD133+ and CD34+ progenitor cells compared to healthy elderly controls independent of cardiovascular risk factors and medication. In addition, the number of circulating CD34+/CD133+ progenitor cells in AD patients was significantly inversely correlated with cognitive function, age, and plasma levels of SDF-1, the most potent chemokine for progenitor cells. Our findings suggest a stage-dependent upregulation of circulating CD34+/CD133+ and CD34+ progenitor cells in AD patients, which could take part in tissue healing processes of the brain in AD.

Glial cell-line derived neurotrophic factor (GDNF) concentrations in cerebrospinal fluid and serum of patients with early Alzheimer's disease and normal controls.

As neurotrophic factors play an important role in development and maintenance of global central nervous system (CNS) function, we supposed that glial cell-line derived neurotrophic factor (GDNF), which has been extensively studied for its survival promoting effects especially concerning catecholaminergic neurons, also plays a significant role in neurodegenerative disease characterized mainly by damage of cholinergic CNS neurons like AD. Here we compared GDNF concentrations in serum and cerebrospinal fluid (CSF) of patients with probable Alzheimer's disease (AD) and normal controls (NC). While GDNF concentrations in CSF were significantly increased in patients with AD (291.7 +/- 85.8 pg/ml) compared with NC subjects (218.7 +/- 93.3 pg/ml, p = 0.012), GDNF concentration of AD patients (486.5 +/- 72.3 pg/ml) in serum were significantly decreased compared with the NC group (711.5 +/- 186.5 pg/ml, p < 0.001). Increased GDNF in CSF of AD might be due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease and/or impairment of CSF turnover. Decreased serum concentration of GDNF might be related to altered function of the blood brain barrier thus disturbing clearance or facilitating passover of potentially harmful metabolites.

Suppression of fibrous scarring in spinal cord injury of rat promotes long-distance regeneration of corticospinal tract axons, rescue of primary motoneurons in somatosensory cortex and significant functional recovery.

Traumatic injury of the central nervous system results in formation of a collagenous basement membrane-rich fibrous scar in the lesion centre. Due to accumulation of numerous axon-growth inhibitory molecules the lesion scar is considered a major impediment for axon regeneration. Following transection of the dorsal corticospinal tract (CST) at thoracic level 8 in adult rats, transient suppression of collagenous scarring in the lesion zone by local application of a potent iron chelator and cyclic adenosine monophosphate resulted in the delay of fibrous scarring. Treated animals displayed long-distance growth of CST axons through the lesion area extending for up to 1.5-2 cm into the distal cord. In addition, the treatment showed a strong neuroprotective effect, rescuing cortical motoneurons projecting into the CST that normally die (30%) after thoracic axotomy. Further, anterogradely traced CST axons regenerated through both grey and white matter and developed terminal arborizations in grey matter regions. In contrast to controls, injured animals receiving treatment showed significant functional recovery in the open field, in the horizontal ladder and in CatWalk locomotor tasks. We conclude that the fibrous lesion scar plays a pivotal role as a growth barrier for regenerating axons in adult spinal cord and that a delay in fibrotic scarring by local inhibition of collagen biosynthesis and basement membrane deposition is a promising and unique therapeutic strategy for treating human spinal trauma.

Dose-dependent rescue of axotomized rat retinal ganglion cells by adenovirus-mediated expression of glial cell-line derived neurotrophic factor in vivo.

Adult rat retinal ganglion cells undergo degeneration after optic nerve transection. Repeated intraocular injection of glial cell-line derived neurotrophic factor (GDNF) has been shown to be efficient in enhancing retinal ganglion cell survival following optic nerve axotomy. In the present study we evaluated the potential survival-promoting effect of adenovirally administered GDNF on axotomized retinal ganglion cells. A single intravitreal injection [7 x 107 plaque-forming units (pfu) or 7 x 108 pfu] of an adenoviral vector expressing the rat GDNF gene from a cytomegalovirus promoter enhanced retinal ganglion cell survival 14 days after axotomy by 67 and 125%, respectively, when compared to control animals. Intraocular administration of the vector rescued 12.6 and 23%, respectively, of the retinal ganglion cells which would otherwise have died after axotomy. An increase in retinal GDNF protein and specific virally transduced GDNF mRNA expression was detected following intraocular vector application. Our data support previous findings showing that adenoviral delivery of neurotrophic factors to the vitreous body is a feasible approach for the prevention of axotomy-induced retinal ganglion cell death in vivo and may constitute a relevant strategy for future treatment in traumatic brain injury and ensuing neurodegeneration.

Potential synergistic protection of retinal ganglion cells from axotomy-induced apoptosis by adenoviral administration of glial cell line-derived neurotrophic factor and X-chromosome-linked inhibitor of apoptosis.

Following transection of the optic nerve (ON) in the adult rat, retinal ganglion cells (RGCs) undergo degeneration, and within 14 days 85% of axotomized RGCs die by apoptosis. Adenoviral delivery of the mammalian caspase inhibitor X-chromosome-linked inhibitor of apoptosis (Ad.XIAP) to the ON stump leads to expression exclusively in RGCs and rescues 18.9% of the RGCs that would degenerate without treatment. Following adenoviral vector injection into the vitreous body, bioactive glial cell line-derived neurotrophic factor (Ad.GDNF) is expressed in the retina and secreted to rescue 22.8% of lesioned RGCs. Here we report that coadministration of Ad.XIAP retrogradely directed to RGCs and intravitreal Ad.GDNF acts synergistically to protect axotomized RGCs. Combination treatment rescued 47.3% of RGCs that would undergo apoptosis without any treatment as opposed to 37.4% that would be expected if the two treatments acted independently. While without treatment only 15% of axotomized RGCs would survive, combination treatment resulted in survival of 55.4% of the total RGC population. These findings underline the neuroprotective potential of synergistic effects of a combination of different treatment strategies.