Apoptotic signals within the basal forebrain cholinergic neurons in Alzheimer's disease

A relatively early and substantial loss of basal forebrain cholinergic neurons is a constant feature of Alzheimer's disease (AD). However, the mechanisms that contribute to the selective vulnerability of these neurons are not fully delineated. In the present series of experiments, we determined the possible contribution of apoptotic processes and other pathologic cascades to the degeneration of the cholinergic neurons of the nucleus basalis of Meynert (NBM) in AD. In contrast to neurons in the frontal cortex which showed prominent DNA fragmentation as detected by the TUNEL method, no DNA fragmentation was observed within the NBM in any of the AD or normal brains. Similarly, immunoreactivity for the apoptotic signals Fas, Fas-ligand, Bax, Bcl-x, caspase-8, caspase-9 and caspase-3 was absent from the NBM of AD and control brains. In contrast, a substantial subpopulation of cholinergic neurons within the NBM in AD displayed prominent immunoreactivity for the apoptotic signal Fas-associated death domain (FADD) in the form of tangles. FADD immunoreactivity was also present in dystrophic neurites. FADD-positive tangle-like structures were localized in neurons which contained immunoreactivity for the cholinergic marker choline acetyltransferase (ChAT) and the low affinity neurotrophin receptor p75NTR. While many of the NBM cholinergic neurons in control brains contained immunoreactivity for the calcium binding protein calbindin-D28K (CB), the NBM neurons in AD displayed a substantial loss of CB immunoreactivity. Importantly, most of FADD-immunoreactive cholinergic neurons were devoid of CB immunoreactivity, and, conversely, most CB-positive cholinergic neurons had no FADD immunoreactivity. FADD immunoreactivity within the basal forebrain was colocalized with phosphorylated tau immunoreactive tangles and dystrophic neurites. In contrast, FADD immunoreactivity did not appear to be related to the primarily diffuse amyloid-beta deposits intermingled between cholinergic neurons in AD NBM. Finally, many CD68-positive microglia were observed surrounding the NBM cholinergic neurons in AD. In conclusion, the findings of the present study indicate that, while the FADD apoptotic signaling pathway may be triggered within the basal forebrain cholinergic neurons in AD, the apoptotic cascade is most likely aborted as no DNA fragmentation was detected and the executioner caspase-3 was not up-regulated within these neurons. The findings also suggest possible relationships between loss of CB, FADD expression and phosphorylation of tau within the basal forebrain cholinergic neurons in AD.     

Postural and gait symptoms in de novo Parkinson's disease patients correlate with cholinergic white matter pathology

IntroductionThe postural instability gait difficulty motor subtype of patients with Parkinson's disease (PIGD-PD) has been associated with more severe cognitive pathology and a higher risk on dementia compared to the tremor-dominant subtype (TD-PD). Here, we investigated whether the microstructural integrity of the cholinergic projections from the nucleus basalis of Meynert (NBM) was different between these clinical subtypes.MethodsDiffusion-weighted imaging data of 98 newly-diagnosed unmedicated PD patients (44 TD-PD and 54 PIGD-PD subjects) and 10 healthy controls, were analysed using diffusion tensor imaging, focusing on the white matter tracts associated with cholinergic projections from the NBM (NBM-WM) as the tract-of-interest. Quantitative tract-based and voxel-based analyses were performed using FA and MD as the estimates of white matter integrity.ResultsVoxel-based analyses indicated significantly lower FA in the frontal part of the medial and lateral NBM-WM tract of both hemispheres of PIGD-PD compared to TD-PD. Relative to healthy control, several clusters with significantly lower FA were observed in the frontolateral NBM-WM tract of both disease groups. Furthermore, significant correlations between the severity of the axial and gait impairment and NBM-WM FA and MD were found, which were partially mediated by NBM-WM state on subjects’ attentional performance.ConclusionsThe PIGD-PD subtype shows a loss of microstructural integrity of the NBM-WM tract, which suggests that a loss of cholinergic projections in this PD subtype already presents in de novo PD patients.     

Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer's disease

Cholinergic neurons were studied by immunohistochemistry, with an antiserum against choline acetyltransferase (ChAT), in the basal forebrain (Ch1 to Ch4) of four patients with Alzheimer's disease (AD) and four control subjects. ChAT-positive cell bodies were mapped and counted in Ch1 (medial septal nucleus), Ch2 (vertical nucleus of the diagonal band), Ch3 (horizontal nucleus of the diagonal band) and Ch4 (nucleus basalis of Meynert). Compared to controls, the number of cholinergic neurons in AD patients was reduced by 50% on average. The interindividual variations in cholinergic cell loss were high, neuronal loss ranging from moderate (27%) to severe (63%). Despite the small number of brains studied, a significant correlation was found between the cholinergic cell loss and the degree of intellectual impairment. To determine the selectivity of cholinergic neuronal loss in the basal forebrain of AD patients, NPY-immunoreactive neurons were also investigated. The number of NPY-positive cell bodies was the same in controls and AD patients. The results (1) confirm cholinergic neuron degeneration in the basal forebrain in AD and the relative sparing of these neurons in some patients, (2) indicate that degneration of cholinergic neurons in the basal forebrain contributes to intellectual decline, and (3) show that, in AD, such cholinergic cell loss is selective, since NPY-positive neurons are preserved in the basal forebrain.     

Multimodal assessment of nigrosomal degeneration in Parkinson's disease

BackgroundApproximately forty percent of all dopaminergic neurons in SNpc are located in five dense neuronal clusters, named nigrosomes. T₂- or T₂*-weighted images are used to delineate the largest nigrosome, named nigrosome-1. In these images, nigrosome-1 is a hyperintense region in the caudal and dorsal portion of the T₂- or T₂*-weighted substantia nigra. In PD, nigrosome-1 experiences iron accumulation, which leads to a reduction in T₂-weighted hyperintensity. Here, we examine neuromelanin-depletion and iron deposition in regions of interest (ROIs) derived from quantitative-voxel based morphometry (qVBM) on neuromelanin-sensitive images and compare the ROIs with nigrosome-1 identified in T₂*-weighted images.MethodsNeuromelanin-sensitive and multi-echo gradient echo imaging data were obtained. R₂* was calculated from multi-echo gradient echo imaging data. qVBM analysis was performed on neuromelanin-sensitive images and restricted to SNpc. Mean neuromelanin-sensitive contrast and R₂* was measured from the resulting qVBM clusters. Nigrosome-1 was segmented in T₂*-weighted images of control subjects and its location was compared to the spatial location of the qVBM clusters.ResultsTwo bilateral clusters emerged from the qVBM analysis. These clusters showed reduced neuromelanin-sensitive contrast and increased mean R₂* in PD as compared to controls. Cluster-1 from the qVBM analysis was in a similar spatial location as nigrosome-1, as seen in T₂*-weighted images.ConclusionqVBM cluster-1 shows reduced neuromelanin-sensitive contrast and is in a similar spatial position as nigrosome-1. This region likely corresponds to nigrosome-1 while the second cluster may correspond to nigrosome-2.     

Regulation of regional cerebral blood flow by cholinergic fibers originating in the basal forebrain

The intracranial neural vasodilative system of cholinergic fibers projecting from the basal forebrain to the cortex was discovered by Biesold, Inanami, Sato and Sato (Biesold, D., Inanami, O., Sato, A., Sato, Y., 1989. Stimulation of the nucleus basalis of Meynert increases cerebral cortical blood flow in rats. Neurosci. Lett. 98, 39-44) using laser Doppler flowmetry in anesthetized rats. This cholinergic vasodilative system, which operates by increasing extracellular ACh release, relies upon activation of both muscarinic and nicotinic cholinergic receptors in the parenchyma of the cortex. Further, the involvement of nitric oxide in this cholinergic vasodilation, indicates the necessity to this system of neurons, which contain nitric oxide synthase. The increase in cortical blood flow elicited by this cholinergic vasodilative system is independent of systemic blood pressure and is not coupled to cortical metabolic rates. This cholinergic vasodilative system may be activated by somatic afferent stimulation. Most of the data presented here were obtained in anesthetized animals.     

Overexpression of neurotrophin receptor p75 contributes to the excitotoxin-induced cholinergic neuronal death in rat basal forebrain

Both excitotoxicity and altered trophic factor support have been implicated in the pathogenesis of Alzheimer's disease. To determine whether stimulation of p75, the low-affinity receptor for nerve growth factor, contributes to the excitotoxin-induced apoptotic death of cholinergic neurons, we examined the effect of unilateral kainic acid (KA; PBS vehicle, 1.25, 2.5 and 5.0 nmol) administration into rat basal forebrain on neuronal loss and p75 expression. KA (2. 5 nmol) destroyed 43% of Nissl-stained neurons and 70% of choline acetyltransferase (ChAT)-positive neurons 5 days after injection. Agarose gel electrophoresis revealed that KA (2.5 nmol) induced local internucleosomal DNA fragmentation after 6-48 h. Immunohistochemical analysis further showed that KA (2.5 nmol) augmented p75 immunoreactivity at a time when terminal transferase-mediated deoxyuridine trophosphate (d-UTP)-digoxigenin nick end labeling (TUNEL)-positive nuclei were increased. Many fragmented nuclei were co-labeled with ChAT antibody. The chronic administration of anti-rat p75 or the protein synthesis inhibitor, cycloheximide, but not anti-human p75, substantially reduced the KA-induced destruction of cholinergic neurons and the induction of internucleosomal DNA fragmentation. Anti-rat p75, but not cycloheximide, also reversed the spatial memory impairment produced by KA. These findings suggest that overexpression of p75 contributes to the excitotoxin-induced death of rat basal forebrain cholinergic neurons by an apoptotic-like mechanism.     

The cholinergic system in mild cognitive impairment and Alzheimer's disease: An in vivo MRI and DTI study

Few studies have investigated in vivo changes of the cholinergic basal forebrain in Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), an at risk stage of AD. Even less is known about alterations of cortical projecting fiber tracts associated with basal forebrain atrophy. In this study, we determined regional atrophy within the basal forebrain in 21 patients with AD and 16 subjects with MCI compared to 20 healthy elderly subjects using deformation‐based morphometry of MRI scans. We assessed effects of basal forebrain atrophy on fiber tracts derived from high‐resolution diffusion tensor imaging (DTI) using tract‐based spatial statistics. We localized significant effects relative to a map of cholinergic nuclei in MRI standard space as determined from a postmortem brain. Patients with AD and MCI subjects showed reduced volumes in basal forebrain areas corresponding to anterior medial and lateral, intermediate and posterior nuclei of the Nucleus basalis of Meynert (NbM) as well as in the diagonal band of Broca nuclei (P < 0.01). Effects in MCI subjects were spatially more restricted than in AD, but occurred at similar locations. The volume of the right antero‐lateral NbM nucleus was correlated with intracortical projecting fiber tract integrity such as the corpus callosum, cingulate, and the superior longitudinal, inferior longitudinal, inferior fronto‐occipital, and uncinate fasciculus (P < 0.05, corrected for multiple comparisons). Our findings suggest that a multimodal MRI‐DTI approach is supportive to determine atrophy of cholinergic nuclei and its effect on intracortical projecting fiber tracts in AD. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Neuropathological study on the nucleus basalis of Meynert in Pick's disease

Summary The pathological changes in the nucleus basalis of Meynert (nbM) in 10 autopsied cases with Pick's disease were studied in comparison with 15 agematched controls. Both the number and density of nerve cells and the degree of fibrillary gliosis were examined at the anterior, intermediate, and posterior divisions of the nbM. In only 2 of the 10 Pick cases was the number of neurons significantly reduced, with moderate fibrillary gliosis at the anterior division (case 5: reduced by 64%, case 8: reduced by 46%). This neuronal loss in the anterior nbM division may not be a retrograde degeneration secondary to the cortical lesions, since there were some cases without neuronal loss in the nbM despite the presence of much more severe cortical lesions than in these two cases. In all Pick cases except case 1, mild to moderate fibrillary gliosis was found without an apparent neuronal loss at the posterior division of the nbM. This change in the posterior nbM division may be due to secondary retrograde degeneration, since there was a parallel relationship between the degree of fibrillary gliosis in the posterior nbM division and the severity of cortical lesions in the temporal tip and the superior temporal gyrus, to which the cholinergic fibers are known to project from the posterior division of the nbM. The present study suggests that the mild degeneration of the nbM in most cases with Pick's disease may be secondary, but that there are also some cases of Pick's disease with a primary degeneration in the nbM.     

Basal ganglia atrophy–associated causal structural network degeneration in Parkinson's disease

Parkinson''s disease (PD) is a progressive neurodegenerative disease characterized by both motor and non‐motor symptoms. A convergent pathophysiological hallmark of PD is an early selective vulnerability within the basal ganglia circuit. However, the causal interactions between basal ganglia atrophy and progressive structural network alterations in PD remain unaddressed. Here, we adopted voxel‐based morphometry method to measure gray matter (GM) volume for each participant (n = 84 PD patients and n = 70 matched healthy controls). Patients were first divided into three stages according to the Hoehn and Yahr (H&Y) and the Part III of Unified Parkinson''s Disease Rating Scale scores respectively to analyze the stage‐specific GM atrophy patterns. Then, the modulation of early caudate atrophy over other brain structures was evaluated using the whole‐brain voxel‐wise and region‐of‐interest‐wise causal structural covariance network approaches. We found that GM atrophy progressively expands from the basal ganglia to the angular gyrus, temporal areas, and eventually spreads through the subcortical–cortical networks as PD progresses. Notably, we identified a shared caudate‐associated degeneration network including the basal ganglia, thalamus, cerebellum, sensorimotor cortex, and cortical association areas with the PD progressive factors. These findings suggest that the early structural vulnerability of basal ganglia in PD may play a pivotal role in the modulation of motor and non‐motor circuits at the structural level. Our work provides evidence for a novel mechanism of network degeneration that underlies the pathology of PD and may have potential clinical applications in the development of early predictors of PD onset and progress.     

Neuropathy and levodopa in Parkinson's disease: Evidence from a multicenter study

The objectives of this study were to evaluate the risk of neuropathy in patients with Parkinson's disease (PD) and to evaluate the role of levodopa exposure as a potential risk factor. A multicenter study of 330 patients with PD and 137 healthy controls with a comparable age distribution was performed. With respect to levodopa exposure, 144 patients had long exposure (≥3 years) to levodopa (LELD), 103 patients had short exposure (<3 years) to levodopa (SELD), and 83 patients had no exposure to levodopa (NOLD). Nerve function was evaluated using the reduced total neuropathy score. Right sural sensory antidromic and peroneal motor nerve conduction studies were performed by neurophysiologists who were blinded to the existence of neuropathy clinical features or PD treatment. Overall, 19.40% of patients in the LELD group, 6.80% in the SELD group, 4.82% in the NOLD group, and 8.76% in the control group were diagnosed with neuropathy (axonal, predominantly sensory). Multivariate logistic analysis indicated that the risk of neuropathy was not influenced by disease duration, severity, or sex. The risk of neuropathy increased by approximately 8% for each year of age (P < 0.001; odds ratio [OR], 1.08; 95% confidence interval [CI], 1.037‐1.128). The risk of neuropathy was 2.38 higher in the LELD group than in the control group (P = 0.022; OR, 2.38; 95% CI, 1.130‐5.014). In a comparison between patients with and without neuropathy (Student's t test), the levodopa dose was higher (P < 0.0001), serum vitamin B12 levels were lower (P = 0.0102), and homocysteine levels were higher (P < 0.001) in the patients with neuropathy. Our results demonstrate that the duration of exposure to levodopa, along with age, is the main risk factor for the development of neuropathy. Screening for homocysteine and vitamin B12 levels and clinical‐neurophysiological monitoring for neuropathy may be advisable in patients with PD who are receiving treatment with levodopa. © 2013 International Parkinson and Movement Disorder Society     

Cognitive profile of Parkinson's disease patients: a comparative study between early-onset and late-onset Parkinson's disease

Aim: To investigate the influence of onset age on the occurrence and progression of cognitive dysfunction using neuropsychological tests and the electrophysiological component P300 in both early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD) patients. Methods: A cohort of 76 EOPD patients and 166 LOPD patients was recruited for this study. Demographic information and clinical features, including age, disease duration, education level, family history, the Unified Parkinson's Disease Rating Scale, the Hoehn and Yahr stage, and depression scores were documented for each patient. The Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA), Wechsler Adult Intelligence Scale – Revised, Chinese version (WAIS-RC) and Wechsler Memory Scale – Revised, Chinese version (WMS-RC) were used. In addition, P300 was also examined to assess cognitive function. Results: Although EOPD patients had longer disease duration, their cognitive dysfunction progressed more slowly. The MoCA tests revealed that EOPD patients had higher scores in visuospatial function, attention, delayed recall, and orientation than the LOPD patients. The difference between the two groups on the WMS-RC test did not reach significance, whereas the scores in executive function, visuospatial function and attention as measured on the WAIS-RC test were significantly lower in the LOPD group. In addition, P300 latencies were markedly delayed and P300 amplitudes were reduced in the LOPD group. Conclusions: The current findings demonstrated that cognitive dysfunction progressed more slowly in the EOPD group. Although the LOPD patients exhibited shorter disease durations, their cognitive abilities, including executive function, visuospatial function and attention, may have been impaired.     

Comparing cerebral perfusion in Alzheimer's disease and Parkinson's disease dementia: an ASL-MRI study

Emerging evidence suggests that Alzheimer''s disease (AD) and Parkinson''s disease dementia (PDD) share neurodegenerative mechanisms. We sought to directly compare cerebral perfusion in these two conditions using arterial spin labeling magnetic resonance imaging (ASL-MRI). In total, 17 AD, 20 PDD, and 37 matched healthy controls completed ASL and structural MRI, and comprehensive neuropsychological testing. Alzheimer''s disease and PDD perfusion was analyzed by whole-brain voxel-based analysis (to assess absolute blood flow), a priori specified region of interest analysis, and principal component analysis (to generate a network differentiating the two groups). Corrections were made for cerebral atrophy, age, sex, education, and MRI scanner software version. Analysis of absolute blood flow showed no significant differences between AD and PDD. Comparing each group with controls revealed an overlapping, posterior pattern of hypoperfusion, including posterior cingulate gyrus, precuneus, and occipital regions. The perfusion network that differentiated AD and PDD groups identified relative differences in medial temporal lobes (AD<PDD) and right frontal cortex (PDD<AD). In conclusion, the pattern of cerebral hypoperfusion is very similar in AD and PDD. This suggests closely linked mechanisms of neurodegeneration mediating the evolution of dementia in both conditions.     

SCOPA‐cognition cutoff value for detection of Parkinson's disease dementia

The SCOPA‐Cognition is a reliable and valid test to evaluate cognitive functioning in Parkinson's disease and is widely used in clinical and research settings. Recently, the Movement Disorder Society introduced criteria for Parkinson's disease dementia. The objective of the present study was to use these criteria to determine SCOPA‐Cognition cutoffs for maximum accuracy, screening, and diagnosing of Parkinson's disease dementia. A total of 282 patients with Parkinson's disease were assessed with the SCOPA‐Cognition and the Movement Disorder Society's Parkinson's disease dementia criteria. From the 275 patients with a complete assessment of the dementia criteria, 12% (n = 32) fulfilled the criteria. Data from 268 patients with complete assessments of both the dementia criteria and the SCOPA‐Cognition were used to determine cutoffs for maximum accuracy, screening, and diagnosing of Parkinson's disease dementia. The area under the curve was 0.91 (95% confidence interval, 0.85–0.97), showing a strong association between the dementia criteria and the SCOPA‐Cognition. The cutoff for maximum accuracy was 22/23, based on the highest sum of sensitivity (0.80) and specificity (0.87), with positive and negative predictive values of 0.43 and 0.97, respectively. The optimal screening cutoff was 24/25, and the optimal diagnostic cutoff was 17/18. Using the recently published Parkinson's disease dementia criteria as a reference, the current study presents SCOPA‐Cognition cutoffs for maximum accuracy, screening, and diagnosing of Parkinson's disease dementia. The availability of SCOPA‐Cognition cutoffs for Parkinson's disease dementia may contribute to the scale's usefulness and promote its further use in both clinical and research settings. © 2011 Movement Disorder Society     

Delusions and visual hallucinations in a patient with Parkinson's disease with dementia showing pronounced Lewy body pathology in the nucleus basalis of Meynert

We describe an autopsy‐proven case of Parkinson's disease with dementia showing early‐onset delusions and hallucinations with limbic‐type Lewy body pathology. A Japanese man 72 years old at time of death, developed hand tremor at the age of 45. On neurological examination at 47 years of age, parkinsonian symptoms and signs were present. Pergolide mesylate 1000 μg/day improved his motor symptoms. Then, delusional jealousy appeared and he consulted the psychiatric department in our hospital at the age of 50. Pergolide mesylate 2000 μg/day and trihexyphenidyl hydrochloride 6 mg/day were prescribed. His delusional jealousy made him hit his wife at the age of 63, and visual hallucinations were demonstrated. Brain magnetic resonance imaging (MRI) at the age of 65 revealed mild frontal lobe atrophy. At the age of 72, apparent dementia and dysphagia appeared. The total clinical course was 27 years. The brain showed mild frontal atrophy and weighed 1295 g before fixation. Depigmentation of the substantia nigra and locus ceruleus was macroscopically apparent. Neuronal loss with gliosis was noteworthy in the substantia nigra, locus ceruleus, dorsal vagal nucleus, nucleus basalis of Meynert (NBM), and intermediate lateral nuclei; however, cerebral neocortex and limbic systems were relatively preserved. Widespread occurrence of Lewy bodies with a few Lewy neurites were demonstrated (limbic‐type). Noticeable Lewy body pathology in the NBM was shown in contrast to that in other limbic system structures, such as the amygdala and parahippocampal gyrus, and cerebral cortex. In vivo structural imaging studies revealed that cholinergic projections from the NBM could be responsible for generation of cholinergic deficiency syndrome, including delusions and hallucinations. Furthermore, basal forebrain volume is reduced in patients with Parkinson's disease showing visual hallucinations. Prominent Lewy body pathology in the NBM could be related to not only visual hallucinations but also delusions.