[Show abstract][Hide abstract] ABSTRACT: Reports of altered endogenous neurogenesis in people with Alzheimer's disease (AD) and transgenic AD models have suggested that endogenous neurogenesis may be an important treatment target, but there is considerable discrepancy among studies. We examined endogenous neurogenesis and glia changes across the range of pathologic severity of AD in people with and without dementia to address this key question.
[Show abstract][Hide abstract] ABSTRACT: Damage to sub-cortical white matter is a key substrate of vascular dementia (VaD) leading to deficits in executive function and cognitive processing speed. Dynamin1 is a 100kDa protein, accounting for 0.4% of the total brain protein, and has a central role in many intracellular processes such as synaptic vesicle trafficking and recycling. In this study, we examined the status of Dynamin1 in the white matter from frontal cortex area. In order to measure the levels of Dynamin1, we isolated cortical white matter from a total of 34 post-mortem brains derived from controls (N=11), mixed Alzheimer's Disease (AD) and VaD (N=8), VaD (N=7), and Stroke no Dementia (SND, N=8) subjects. A commercial ELISA kit was then used to determine the level of Dynamin1. In comparison to controls, Dynamin 1 was elevated in patients SND (+400%) and reduced in patients with mixed VaD (-50%). Furthermore, levels of Dynamin 1 were significantly associated with preserved cognition as indicated by the MMSE and CAMCOG and upregulation of vesicular Glutamate transporter 1. This work indicates that Dynamin 1 is associated with both preserved cognition and regenerative responses in older people with cerebrovascular disease and may represent a novel treatment target.
[Show abstract][Hide abstract] ABSTRACT: Functional neuroimaging studies have consistently reported abnormalities in the visual cortex in patients with dementia with Lewy bodies (DLB), but their neuropathologic substrates are poorly understood. We analyzed synaptic proteins and choline acetyltransferase (ChAT) in the primary (BA17) and association (BAs18/19) visual cortex in DLB and similar aged control and Alzheimer disease (AD) subjects. We found lower levels of synaptophysin, syntaxin, SNAP-25, and γ-synuclein in DLB subjects versus both aged control (68%-78% and 27%-72% for BA17 and BAs18/19, respectively) and AD cases (54%-67% and 10%-56% for BA17 and BAs18/19, respectively). The loss in ChAT activity in DLB cases was also greater in BA17 (72% and 87% vs AD and control values, respectively) than in BAs18/19 (52% and 65% vs AD and control groups, respectively). The observed synaptic and ChAT changes in the visual cortices were not associated with tau or β-amyloid pathology in the occipital or the frontal, temporal, and parietal neocortex. However, the neocortical densities of LBs, particular those in BA17 and BAs18/19, correlated with lower synaptic and ChAT levels in these brain areas. These findings draw attention to molecular changes within the primary visual cortex in DLB and correlate with the neuroimaging findings within the occipital lobe in patients with this disorder.
Journal of neuropathology and experimental neurology. 01/2013; 72(1):53-60.
[Show abstract][Hide abstract] ABSTRACT: Neurogenesis occurs in the subventricular zone and the sub-granular layer of the hippocampus and is thought to take place in 5 stages, including proliferation, differentiation, migration, targeting, and integration phases, respectively. In Alzheimer's disease (AD) both increased and decreased neurogenesis has been reported and cholinergic activity is assumed to be involved in neurogenesis. The aim of this study was to systematically assess different phases of neurogenesis and their relation to AD and cholinergic pathology. We investigated post-mortem brain tissue from 20 AD patients and 21 non-demented controls that was neuropathologically characterized according to standardized criteria. Hippocampal sections were stained with antibodies against neurogenic markers Musashi-1, nestin, PSA-NCAM, doublecortin, and β-III-tubulin as well as ChAT (choline-acetyltransferase). Using image analysis immunoreactivity was assessed in the subventricular zone, the sub-granular layer, and the granule cell layer by determining the integrated optical density. In the sub-granular layer and the granule cell layer Musashi-1 and ChAT immunoreactivities were significantly lower in AD and decreased with increasing Braak stages. Conversely, immunorreactivities of both nestin and PSA-NCAM were significantly higher in AD and increased with increasing Braak stages while no changes were seen for doublecortin and β-III-tubulin, except for significantly higher doublecortin levels in the granule cell layer of AD cases. Of note, Musashi-1 immunoreactivity significantly correlated with ChAT immuonoreactivity across different Braak stages. In the subventricular zone only nestin immunoreactivity was significantly higher in AD and significantly increased with increasing Braak stages, while no significant differences were seen for all other markers. Our finding of a reduction of ChAT and Musashi-1 levels in AD is compatible with the assumption that cholinergic pathology per se has a detrimental influence on neurogenesis. We conclude that neurogenic abnormalities in AD differ between phases and areas of neurogenesis and stages of AD; while hippocampal stem cells (Musashi-1) decrease, proliferation (nestin) increases and differentiation/migration phase as well as axonal/dendritic targeting (doublecortin and β-III-tubulin) remains virtually unchanged. This suggests an attenuation of stem cells together with compensatory increased proliferation that, however, does not result in an increased number of migratory neuroblasts and differentiated neurons in AD.
Neurobiology of Disease 04/2012; 47(2):155-62. · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent work has highlighted a significant increase of neural stem/progenitor cells after stroke in humans. In this study, we examined neurogenesis in small vessel disease, a key concurrent pathology in Alzheimer's disease.
We assayed autopsy tissue from 13 vascular dementia patients with small vessel disease and 12 age-matched subjects without cerebrovascular pathology, undertaking immunohistochemistry in the affected brain area and the subventricular zone with a well-characterized battery of antibodies to detect neural stem cells/progenitors and immature neurones, as well as choline acetyltransferase immunoreactivity.
We showed significant increases ranging from 33% to 92% (P < 0.05) in neural progenitor cells around the areas of microvascular pathology and in the subventricular zone in patients with small vessel disease compared to individuals without cerebrovascular changes, even in patients with severe cerebrovascular disease, as defined by neuropathological assessment. Some of the progenitor cells give rise to immature neurones in the affected areas. These alterations were associated with vascular changes, but were unrelated to the cholinergic deficit observed in the cortex and subventricular zone in these patients, in contrast to other dementias examined such as dementia with Lewy bodies.
This study provides evidence for neurogenesis in small vessel disease and may have important implications for the development of new therapies for neurodegenerative diseases.
Neuropathology and Applied Neurobiology 10/2011; 38(4):344-53. · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dementia with Lewy bodies (DLB) is associated with alpha synuclein pathology and slowly progressive dementia. Progenitor abnormalities have previously been reported in the subventricular zone (SVZ) adjacent to the lateral ventricle. To evaluate changes in neural stem cells and progenitors in the hippocampal neurogenic niche, immunohistochemistry (IHC) using the neural stem cell markers Musashi 1, nestin, proliferating cell nuclear antigen (PCNA), doublecortin, and glial fibrillary acidic protein (GFAP) were examined in age-matched control and DLB groups. Staining was quantified in the hippocampal SVZ, subgranular layer (SGL) and ependymal cell layer (EPL). There was a significant loss in DLB of Musashi 1 (P < 0.01) in all areas, an increase in PCNA in hippocampal SVZ (P = 0.01) and SGL (P = 0.05), and an increase in doublecortin in the hippocampal SVZ (P = 0.04) and EPL (P = 0.02). This is the first report of the changes in neurogenic markers in the hippocampal SVZ and EPL in DLB and may offer the potential for understanding disease pathology and in the devising of treatment.
[Show abstract][Hide abstract] ABSTRACT: Dementia pathologies such as Alzheimer's disease (AD) are reaching epidemic proportions, yet they are not successfully managed by effective symptomatic treatments. Only five drugs have been developed to alleviate cognitive symptoms, and more effective and safe treatments are needed for both the cognitive symptoms and behavioural and psychological symptoms of dementia (BPSD). As two of these licensed drugs (cholinesterase inhibitors [ChEIs]) are naturally derived (galantamine and rivastigmine), the potential for plants to yield new therapeutic agents has stimulated extensive research to discover new ChEIs together with plant extracts, phytochemicals and their derivatives with other mechanistic effects relevant to dementia treatment. This review presents the potential and actual therapeutic strategies for dementia in relation to the known mechanisms of dementia pathology. Phytochemicals that have shown mechanistic effects relevant to the pathological targets in dementia are discussed, with an emphasis on those showing positive clinical trial evidence. Those phytochemicals discussed include the alkaloid physostigmine, a ChEI from the calabar bean (Physostigma venenosum), which has been used as a template for the development of synthetic derivatives that inhibit acetylcholinesterase, including the drug rivastigmine. Also discussed are other ChEI alkaloids including huperzine A, from Huperzia serrata, and galantamine, originally from the snowdrop (Galanthus woronowii); both alkaloids improve cognitive functions in AD patients. Other phytochemicals discussed include cannabinoids (e.g. cannabidiol) from Cannabis sativa, which are emerging as potential therapeutic agents for BPSD, and resveratrol (occurs in various plants) and curcumin (from turmeric [Curcuma longa]), which have been investigated for their pharmacological activities relevant to dementia and their potential effects on delaying dementia progression. The review also discusses plant extracts, and their known constituents, that have shown relevant mechanistic effects for dementia and promising clinical data, but require more evidence for their clinical efficacy and safety. Such plants include Ginkgo biloba, which has been extensively studied in numerous clinical trials, with most outcomes showing positive effects on cognitive functions in dementia patients; however, more reliable and consistent clinical data are needed to confirm efficacy. Other plants and their extracts that have produced promising clinical data in dementia patients, with respect to cognition, include saffron (Crocus sativus), ginseng (Panax species), sage (Salvia species) and lemon balm (Melissa officinalis), although more extensive and reliable clinical data are required. Other plants that are used in traditional practices of medicine have been suggested to improve cognitive functions (e.g. Polygala tenuifolia) or have been associated with alleviation of BPSD (e.g. the traditional prescription yokukansan); such remedies are often prescribed as complex mixtures of different plants, which complicates interpretation of pharmacological and clinical data and introduces additional challenges for quality control. Evidence for the role of natural products in disease prevention, the primary but considerably challenging aim with respect to dementia, is limited, but the available epidemiological and clinical evidence is discussed, with most studies focused on ChEIs, nicotine (from Nicotiana species), curcumin, wine polyphenols such as resveratrol and G. biloba. Challenges for the development of phytochemicals as drugs and for quality control of standardized plant extracts are also considered.
[Show abstract][Hide abstract] ABSTRACT: Comparing the phenomenology, neurochemical pathology, and psychopharmacology of hallucinations and dreaming is limited by the available data. Evidence to date reveals no simple correspondence between the two states. Differences in the phenomenology of visual hallucinations and the visual component of dreams may reflect variations in visual context acting on the same underlying mechanism - the minimal visual input during dreaming contrasts with the more substantial perceived context in hallucinations. Variations in cholinergic, dopaminergic and serotonergic neurotransmitter function during sleep and during hallucinations in Lewy body dementias, together with relevant drug effects suggest that, on the whole, different, potentially opposite, changes characterise the two states. A similar analysis of other psychotic features in Lewy body dementia and other disorders suggests that, in contrast to hallucinations, there may be more convincing parallels between dreaming and delusional states.
Consciousness and Cognition 04/2011; 20(4):1016-20. · 2.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia. Among many other neuropathological changes in DLB, brain region-specific cellular deficits have been reported. They include decreases in motor neuron and pyramidal cell densities, while neocortical parvalbumin (parv)-containing neurons are thought to be free of Lewy bodies and spared in DLB. However, elevated parv levels are found in the cerebrospinal fluid of patients suffering from dementia with Lewy bodies. We performed an immunohistochemical analysis of hippocampal parv-immunoreactive neurons in well-characterised DLB cases and from controls using a specific antibody against the calcium binding protein. In addition, an analysis of the regional and cellular distribution of alpha-synuclein was carried out. Subfield and laminar distribution of parv-immunoreactive (ir) neurons on the hippocampus in subjects with DLB and controls were present exclusively as non-granule cells of the dentate gyrus (DG)/hilus and non-pyramidal cells of CA1, CA2, CA3 and CA4 areas of the hippocampus. The distribution patterns did not differ qualitatively between DLB and controls. Quantitative estimation of parv-ir neuron density revealed significant decreases in the dentate (DG)/hilus region as well as in the CA1 subfield. Double immunolabelling experiments showed that only 2% of parv expressing interneurons were laden with alpha-synuclein immunoreactive material. No significant changes were found for the total neuron densities in DLB cases. Our results show a partial loss of parv-expressing hippocampal interneurons in DLB, which might be the result of long-lasting calcium overload in combination with a proposed impaired mitochondrial function. It remains to be elucidated if the numerical decrease of this particular subset of hippocampal interneurons has consequences for the gamma (20-80 Hz) frequency activity in DLB patients.
[Show abstract][Hide abstract] ABSTRACT: Behavioural and psychological symptoms (BPSD) are frequent in people with Alzheimer's disease and cause considerable stress to patients and their carers. Antipsychotics have been widely used as a first-line treatment, resulting in an estimated 1,800 excess strokes and 1,600 excess deaths in the UK alone. Safe and effective alternatives are urgently needed. Based upon preliminary evidence from clinical trials, aromatherapy with melissa oil may be such an alternative, but initial studies have been modest in size, and adequate blinding has been problematic. Our objective was to assess the efficacy of melissa aromatherapy in the treatment of agitation in people with Alzheimer's disease in an adequately powered and robustly blinded randomized controlled trial comparing it with donepezil, an anticholinesterase drug used with some benefit to treat BPSD.
The study was a double-blind parallel-group placebo-controlled randomized trial across 3 specialist old age psychiatry centres in England. Participants had probable or possible Alzheimer's disease, were resident in a care home, had clinically significant agitation (defined as a score of 39 or above on the Cohen Mansfield Agitation Inventory) and were free of antipsychotics and/or anticholinesterase for at least 2 weeks. Participants were allocated to 1 of 3 groups: placebo medication and active aromatherapy; active medication and placebo aromatherapy or placebo of both.
The primary outcome measure was reduction in agitation as assessed by the Pittsburgh Agitation Scale (PAS) at 4 weeks. This is an observational scale, and raters were required to wear nose clips to ensure that full blinding was maintained. The PAS, Neuropsychiatric Inventory (NPI; another measure of BPSD) and other outcome measures were completed at baseline, 4-week and 12-week follow-ups. 114 participants were randomized, of whom 94 completed the week 4 assessment and 81 completed the week 12 assessment. Aromatherapy and donepezil were well tolerated. There were no significant differences between aromatherapy, donepezil and placebo at week 4 and week 12, but importantly there were substantial improvements in all 3 groups with an 18% improvement in the PAS and a 37% improvement in the NPI over 12 weeks.
When assessed using a rigorous design which ensures blinding of treatment arms, there is no evidence that melissa aromatherapy is superior to placebo or donepezil, in the treatment of agitation in people with Alzheimer's disease. However, the sizeable improvement in the placebo group emphasizes the potential non-specific benefits of touch and interaction in the treatment of agitation in people with Alzheimer's disease.
[Show abstract][Hide abstract] ABSTRACT: There has been recent interest in the possibility that impaired neurogenesis may contribute to the decline in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). We have investigated the effects of commonly used treatments for PD on neural stem cell (NSC) activity in nondemented patients. Postmortem of brain tissue containing the subventricular zone (SVZ) and ependymal layer cells was obtained from 32 nondemented patients with PD. NSC activity was assessed by immunohistochemical staining for RNA-binding protein Musashi1. Regression analyses were then used to identify which clinical factors independently influenced NSC activity. Disease duration was negatively associated with SVZ Musashi1 staining, whereas lifetime levodopa was positively associated in this region. Our findings suggest a positive impact of chronic L-dopa use on the number of NSC in the SVZ of PD patients, which may have relevance for future studies on neuroprotection in neurodegenerative diseases.
Movement Disorders 01/2011; 26(1):45-50. · 5.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An escalating "epidemic" of diseases like Alzheimer's has not yet been met by effective symptomatic treatments or preventative strategies. Among a few current prescription drugs are cholinesterase inhibitors including galantamine, originating from the snowdrop. Research into ethnobotanicals for memory or cognition has burgeoned in recent years. Based on a multi-faceted review of medicinal plants or phytochemicals, including traditional uses, relevant bioactivities, psychological and clinical evidence on efficacy and safety, this overview focuses on those for which there is promising clinical trial evidence in people with dementia, together with at least one other of these lines of supporting evidence. With respect to cognitive function, such plants reviewed include sage, Ginkgo biloba, and complex mixtures of other traditional remedies. Behavioral and psychological symptoms of dementia (BPSD) challenge carers and lead to institutionalization. Symptoms can be alleviated by some plant species (e.g., lemon balm and lavender alleviate agitation in people with dementia; St John's wort treats depression in the normal population). The ultimate goal of disease prevention is considered from the perspective of limited epidemiological and clinical trial evidence to date. The potential value of numerous plant extracts or chemicals (e.g., curcumin) with neuroprotective but as yet no clinical data are reviewed. Given intense clinical need and carer concerns, which lead to exploration of such alternatives as herbal medicines, the following research priorities are indicated: investigating botanical agents which enhance cognition in populations with mild memory impairment or at earliest disease stages, and those for BPSD in people with dementia at more advanced stages; establishing an ongoing authoritative database on herbal medicine for dementia; and further epidemiological and follow up studies of promising phytopharmaceuticals or related nutraceuticals for disease prevention.
[Show abstract][Hide abstract] ABSTRACT: Autism is a neurodevelopmental disorder characterised by impaired social skills, communication deficits and repetitive behaviours.
Alterations in a variety of transmitter signaling systems including serotonin, oxytocin, gamma-aminobutyric acid (GABA), glutamate,
and acetylcholine have been reported in autistic individuals. These are potentially relevant to psychoneuropharmacological
An interesting hypothesis regarding transmitter signaling in autism implicates an imbalance in the major executive excitatory
and inhibitory impulses in the premature autistic brain, combined with defects in secondary neurotransmitter systems, to cause
autistic traits. In this chapter we concentrate on the cholinergic changes investigated in autism based on brain bank tissue.
There is significant reduction in muscarinic and nicotinic receptors in various neocortical areas, including frontal and parietal
neocortex, thalamus, as well as cerebellum in autistic subjects. In contrast, the level of choline acetyltransferase is not
altered, suggesting that the presynaptic cholinergic projections are spared. The cholinergic receptor changes could be caused
by abnormal cortical neuronal morphology (including synaptic and dendritic abnormalities, as well as neuronal migrational
Although a wide range of drugs are used to ameliorate symptoms of autistic behaviour, currently there is no effective treatment.
We discuss novel treatments such as use of cholinesterase inhibitors and nicotinic receptor antagonists as intervention therapies
for treatment of the cognitive and non-cognitive changes in the autistic spectrum disorders.
[Show abstract][Hide abstract] ABSTRACT: Since groundbreaking studies demonstrated the presence of progenitor cells in the adult human brain, there have been intense interests in their potential therapeutic application, but to date only limited data has been obtained in man. An immunohistological study was performed in order to examine neurogenesis in both the subventricular and peri-infarct zones of vascular dementia patients compared to age-matched controls. The results were striking, showing a significant increase of progenitor cells in both the subventricular zone and in peri-infarct area in patients with vascular dementia compared to controls, which was sustained even in patients with infarcts occurring more than three months prior to autopsy. Moreover, the peri-infarct response appeared to be unified with that of the subventricular zone via a stream of cells, with some of them differentiating into immature neurons. We conclude that neurogenesis is stimulated in vascular dementia patients and, specifically, in patients with visible infarcts. Progenitors may migrate from the neurogenic niche to areas of infarction and differentiate into neurons, even three months after cerebrovascular damage, thus implicating the feasibility of enhancing neurogenesis as a novel treatment approach.
Neurobiology of aging 02/2010; 32(12):2152-61. · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate normalized I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) single photon emission computed tomography (SPECT) imaging, a marker for the alpha4beta2 nicotinic receptor, as a predictor of cognitive progression in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB).
Thirty-one patients with dementia (16 patients with AD and 15 patients with DLB) underwent I-5IA-85380 SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM2), which involved spatial preprocessing of scans to standard Montreal Neurological Institute space and intensity normalization of each image to its mean global brain activity.
Regression analysis revealed that reduced normalized I-5IA-85380 uptake in left superior, middle, and inferior frontal gyri and prepost central and anterior cingulate regions significantly correlated with decline in executive function in a pooled group comprising AD and DLB.
The findings, although preliminary, suggest that the cholinergic system may be more involved in neurodegenerative processes affecting some cognitive processes more than others, as such, this procedure may be useful for increased understanding of the pathophysiological mechanisms responsible for neurodegeneration.
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 01/2010; 18(1):86-90. · 3.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: More than 750,000 of the UK population suffer from some form of cognitive impairment and dementia. Of these, 5-20% will have Dementia with Lewy Bodies (DLB). Clinico-pathological studies have shown that it is the low frequency of DLB clinical core features that makes the DLB diagnosis hardly recognisable during life, and easily misdiagnosed for other forms of dementia. This has an impact on the treatment and long-term care of the affected subjects. Having a biochemical test, based on quantification of a specific DLB biomarker within Cerebrospinal Fluid (CSF) could be an effective diagnostic method to improve the differential diagnosis. Although some of the investigated DLB CSF biomarkers are well within the clinical criteria for sensitivity and specificity (>90%), they all seem to be confounded by the contradictory data for each of the major groups of biomarkers (α-synuclein, tau and amyloid proteins). However, a combination of CSF measures appear to emerge, that may well be able to differentiate DLB from other dementias: α-synuclein reduction in early DLB, a correlation between CSF α-synuclein and Aβ42 measures (characteristic for DLB only), and t-tau and p-tau181 profile (differentiating AD from DLB).
International journal of Alzheimer's disease. 01/2010; 2010:536538.
[Show abstract][Hide abstract] ABSTRACT: The complex pathology of Alzheimer's disease is reviewed in relation to: structural abnormalities such as plaques, tangles and synapse loss; disturbances of the cholinergic, noradrenergic, 5-HT and peptide neurotransmitter systems; the involvement of specific proteins including amyloid precursor protein and microtubule-associated tau; signal transduction systems; and neurotrophic factors. Comparisons are made between classical Alzheimer's disease and Lewy body dementia, which differ in respect to the incidence of psychosis, episodic disturbances of consciousness, the extent of the cholinergic abnormality and the occurrence of both Lewy bodies and tangles—differences which are likely to be of practical importance in relation to the design of rational therapy. Current trends in dementia therapy, assessed on the basis of remits of recent drug trials, generally indicate some benefits with many of the different agents being tested, and emphasize the existence of subgroups of responders. The importance of appreciating the heterogeneity of the pathological process in the future design of dementia therapy is highlighted
International Review of Psychiatry 07/2009; 5(4):363-380. · 1.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cholinesterase inhibitors (ChEIs) are widely used for the symptomatic treatment of Alzheimer’s disease (AD). In vitro and
in animal studies, ChEIs have been shown to influence the processing of Aβ and the phosphorylation of tau, proteins that are
the principal constituents of the plaques and neurofibrillary tangles, respectively, in AD brain. However, little is known
about the effects of these drugs on Aβ and tau pathology in AD. Using avidin-biotin immunohistochemistry and computer-assisted
image analysis, we compared Aβ and tau loads in the frontal and temporal cortices of 72 brains from matched cohorts of AD
patients who had or had not received ChEIs. Patients treated with ChEIs had accumulated significantly more phospho-tau in
their cerebral cortex than had untreated patients (P=0.004). Aβ accumulation was reduced but not significantly. These data raise the possibility that increased tau phosphorylation
may influence long-term clinical responsiveness to ChEIs.
Journal of Neurology 05/2009; 256(5):717-720. · 3.84 Impact Factor