Efficacy and safety of memantine in Lewy body dementia

Lewy body dementia (LBD) is a progressive brain disease manifest as dementia and parkinsonism, along with psychotic and autonomic disorders. Although studies in recent years have demonstrated the positive effects of cholinesterase inhibitors in LBD, the search for therapeutic agents with other mechanisms of action remains relevant. An open, controlled, 16-week study was performed with the aim of evaluating the efficacy and safety of memantine in patients with clinically diagnosed LBD (criteria of McKeith et al., 1999). The study included 23 patients (mean age 69.2 ± 5.9 years), who were divided into two groups: 14 patients received memantine at a dose of 20 mg/day and nine patients constituted the control group. Efficacy was evaluated using a battery of quantitative neurospychological tests, clinical scales for assessment of fluctuations in mental states, scales for assessment of behavioral and psychotic disorders, and the general clinical impression scale. The results demonstrated that memantine had positive effects on the patients’ general status and cognitive functions (increases on the mini mental state examination by 1.5 points), mainly because of improvements in attention and control functions. There were also reductions in the severity of fluctuations in mental state, aggressivity, lack of spontaneity, and disinhibition. The severity of psychotic and motor disorders did not change significantly. Tolerance of the agent was good, only two patients withdrawing from the study because of episodes of confusion during the dose titration period. Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 108, No. 5, pp. 39–46, May, 2008.     

Clinicopathological outline of dementia with Lewy bodies applying the revised criteria: the Hisayama study

To explore the validity of the criteria for dementia with Lewy bodies (DLB) revised in 2005, we examined community based consecutive autopsy cases. 10.3% of the non-demented subjects and 31.2% of the demented subjects showed the Lewy body pathology. Applying the revised pathological criteria to the 205 demented subjects, the types of LB pathology of 11 cases (5.4%) were brainstem-predominant, 24 cases (11.7%) were limbic type and 24 cases (11.7%) were diffuse neocortical type, although there were many subjects not to fit the criteria exactly. The prevalence of Lewy bodies (LBs) was almost same regardless of gender; however, the extent of the LB pathology among females was more severe than that in males. The likelihood of DLB being modified by concomitant Alzheimer's pathology was as follows: 27 cases (13.2%) showed low likelihood, 16 cases (7.8%) showed intermediate likelihood and 16 cases (7.8%) showed high likelihood. Since the numbers of clinical features of DLB were significantly higher in the pathological intermediate and high likelihood DLB groups than in the low likelihood DLB group or no LB group, both the intermediate and high likelihood groups of DLB should be considered as pathological DLB.     

Boston naming performance distinguishes between Lewy body and Alzheimer''s dementias

Although naming impairment is common among persons with dementia, little is known about how specific error types on naming tasks may differ between dementias. Recent research has suggested that persons with dementia with Lewy bodies (DLB) have more visuospatial/visuoperceptual dysfunction than those with Alzheimer's disease (AD), which may impact their ability to correctly perceive and name objects. Our retrospective study evaluated the presence and frequency of error types among patients with DLB and AD on the Boston Naming Test (BNT). Errors on the BNT were classified into five types (i.e., visuoperceptual, semantic, phonemic, no response, and other), and performance was compared among 31 probable DLB patients and 31 probable AD patients matched for age, gender, education, and overall dementia severity. AD patients' overall performance on the BNT was significantly worse than DLB patients (p<.05). In terms of error types, DLB patients made significantly more visuoperceptual errors (p<.05) while AD patients made significantly more semantic errors (p<.001). Logistic regression revealed that the number of visuoperceptual and semantic errors significantly predicted group membership (p<.005), with an accuracy of up to 85%. Results suggest that error analysis of BNT responses may be useful in distinguishing between patients with DLB and AD.     

TDP‐43 pathology in Alzheimer's disease,dementia with Lewy bodies and ageing

Intracellular inclusions consisting of TAR DNA binding protein‐43 (TDP‐43 pathology) are present in up to 57% of Alzheimer's disease (AD) cases and follow a distinct topographical pattern of progression described in the TDP‐43 in AD staging scheme. This scheme has not been applied to the assessment of TDP‐43 pathology in dementia with Lewy bodies (DLB) and aged controls. We investigated TDP‐43 pathology prevalence and severity in AD, DLB, mixed AD/DLB (Mx AD/DLB) and aged controls. One hundred and nineteen human post‐mortem brains were included, neuropathologically diagnosed as AD: 46, DLB: 15, Mx AD/DLB: 19 and aged controls: 39. Paraffin sections inclusive of the amygdala, hippocampus, striatum and neocortex were immunohistochemically stained with antibodies against phosphorylated TDP‐43 and staged according to the TDP‐43 in AD staging scheme. TDP‐43 pathology was present in all groups: AD: 73.9%, DLB: 33.3%, Mx AD/DLB: 52.6% and controls: 17.9%. Prevalence of TDP‐43 pathology was significantly higher in AD and Mx AD/DLB compared to controls. In controls, higher age at death was associated with prevalence of TDP‐43 pathology and higher TDP‐43 in AD stage, suggesting that this type of TDP‐43 pathology may partly be an age‐associated phenomenon. Significantly higher prevalence of TDP‐43 pathology in the AD group indicates that AD pathology possibly triggers and aggravates TDP‐43 pathology. The validity of the TDP‐43 in AD staging scheme is not limited to AD and should be applied to assess TDP‐43 pathology in post mortem brains of aged individuals to further elucidate the role of TDP‐43 pathology in age associated neurodegeneration.     

Degeneration of dementia with Lewy bodies measured by diffusion tensor imaging

Dementia with Lewy bodies (DLB) is the second most common form of dementia. It is thought to involve impairment of the visual association area. In this study, we applied diffusion tensor imaging (DTI) to examine the microstructural interruption of visual association areas in patients with DLB. The DTI metrics of three visual association fibres – the inferior longitudinal fasciculus (ILF), visual pathway, and splenial fibres – were compared between 14 patients with DLB and 13 healthy subjects. The fractional anisotropy value of the ILF was significantly lower in patients with DLB than in healthy subjects. The difference in the mean diffusivity value of ILF was at trend level. The λ₂,₃ of ILF were significantly lower in patients with DLB; however, there was no difference in λ₁. DTI metrics of the visual pathway and splenial fibres showed no differences between the groups. Our results showed degeneration of the ILF, which is responsible for visuospatial cognition. ILF dysfunction may influence the clinical features in DLB. Copyright © 2008 John Wiley & Sons, Ltd.     

Comparative Analysis of Cognitive Impairments in Lewy Body Dementia and Alzheimer's Disease

Neuropsychological studies of 50 patients with Lewy body dementia (LBD) and 50 patients with Alzheimer's disease (AD) were performed to assess the characteristics of the cognitive impairments in these diseases. In patients with dementias of similar severities, patients with LBD showed greater impairment of executive and visuospatial functions and had more marked neurodynamic dysfunction. Patients with AD showed more profound memory disorders. __________ Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 105, No. 1, pp. 20–24, January, 2005.     

Clinical correlates of pathology in the claustrum in Parkinson's disease and dementia with Lewy bodies

Dementia and visual hallucinations are common complications of Parkinson's disease (PD), yet their patho-anatomical bases are poorly defined. We studied α-synuclein (αSyn), tau and amyloid-β (Aβ) pathology in the claustrum of 20 PD cases without dementia, 12 PD cases with dementia (PDD) and 7 cases with dementia with Lewy bodies (DLB). αSyn positivity was observed in 75% of PD cases without dementia and in 100% of PDD and DLB cases. Aβ was observed in the claustrum in 25% of PD, 58% of PDD and 100% of DLB cases. Tau was negligible in all cases restricting further analysis. Compared to PD cases without dementia, PDD cases demonstrated a significantly greater αSyn burden in the claustrum (p = 0.0003). In addition, DLB cases showed a significantly increased αSyn deposition when compared to PDD (p = 0.02) and PD without dementia (p = 0.0002). A similar hierarchy, PD < PDD < DLB was seen in terms of Aβ burden in the claustrum. Comparison of αSyn and Aβ burden in those cases with and without visual hallucinations did not reveal any significant associations (p = 0.13 and 0.1, respectively). We demonstrate that pathology in the claustrum, a region of largely obscure physiological function, strongly relates to the presence of dementia in Parkinson's disease and DLB.     

RAB39B is redistributed in dementia with Lewy bodies and is sequestered within aβ plaques and Lewy bodies

Loss of function mutations within the vesicular trafficking protein Ras analogy in brain 39B (RAB39B) are associated with rare X‐linked Parkinson’s disease (PD). Physiologically, RAB39B is localized to Golgi vesicles and recycling endosomes and is required for glutamatergic receptor maturation but also for alpha‐Synuclein (aSyn) homeostasis and the inhibition of its aggregation. Despite evidence linking RAB39B to neurodegeneration, the involvement of the protein in idiopathic neurodegenerative diseases remains undetermined. Here, analysis of the spatial distribution and expression of RAB39B was conducted in post‐mortem human brain tissue from cases of dementia with Lewy bodies (DLB, n = 10), Alzheimer’s disease (AD, n = 12) and controls (n = 12). Assessment of cortical RAB39B immunoreactivity using tissue microarrays revealed an overall reduction in the area of RAB39B positive gray matter in DLB cases when compared to controls and AD cases. Strikingly, RAB39B co‐localized with beta‐amyloid (Aβ) plaques in all cases examined and was additionally present in a subpopulation of Lewy bodies (LBs) in DLB. Biochemical measures of total RAB39B levels within the temporal cortex were unchanged between DLB, AD and controls. However, upon subcellular fractionation, a reduction of RAB39B in the cytoplasmic pool was found in DLB cases, alongside an increase of phosphorylated aSyn and Aβ in whole tissue lysates. The reduction of cytoplasmic RAB39B is consistent with an impaired reserve capacity for RAB39B‐associated functions, which in turn may facilitate LB aggregation and synaptic impairment. Collectively, our data support the involvement of RAB39B in the pathogenesis of DLB and the co‐aggregation of RAB39B with Aβ in plaques suggests that age‐associated cerebral Aβ pathology may be contributory to the loss of RAB39B. Thus RAB39B, its associated functional pathways and its entrapment in aggregates may be considered as future targets for therapeutic interventions to impede the overall pathological burden and cellular dysfunction in Lewy body diseases.     

Regional Multiple Pathology Scores Are Associated with Cognitive Decline in Lewy Body Dementias

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by the presence of α‐synuclein‐containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimer's disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α‐synuclein, phosphorylated tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi‐quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α‐synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α‐synuclein‐positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α‐synuclein‐induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.     

Multimodality imaging characteristics of dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease (AD). Our objective was to determine whether the (11)C-Pittsburgh Compound-B (PiB) retention and regional hypometabolism on positron emission tomography (PET) and regional cortical atrophy on magnetic resonance imaging (MRI) are complementary in characterizing patients with DLB and differentiating them from AD. We studied age-, gender-, and education-matched patients with a clinical diagnosis of DLB (n = 21), AD (n = 21), and cognitively normal subjects (n = 42). Hippocampal atrophy, global cortical PiB retention and occipital lobe metabolism in combination distinguished DLB from AD better than any of the measurements alone (area under the receiver operating characteristic = 0.98). Five of the DLB and AD patients who underwent autopsy were distinguished through multimodality imaging. These data demonstrate that magnetic resonance imaging and PiB positron emission tomography contribute to characterizing the distinct pathological mechanisms in patients with AD compared with DLB. Occipital and posterior parietotemporal lobe hypometabolism is a distinguishing feature of DLB and this regional hypometabolic pattern is independent of the amyloid pathology.     

Alteration of Upstream Autophagy‐Related Proteins (ULK1, ULK2, Beclin1, VPS34 and AMBRA1) in Lewy Body Disease

Autophagy is associated with the pathogenesis of Lewy body disease, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). It is known that several downstream autophagosomal proteins are incorporated into Lewy bodies (LBs). We performed immunostaining and Western blot analysis using a cellular model of PD and human brain samples to investigate the involvement of upstream autophagosomal proteins (ULK1, ULK2, Beclin1, VPS34 and AMBRA1), which initiate autophagy and form autophagosomes. Time course analysis of cultured cells transfected with flag‐α‐synuclein and synphilin‐1 revealed upregulation of these upstream proteins with accumulation of LB‐like inclusions. In human specimens, only mature LBs were positive for upstream autophagosomal proteins. Western blotting of fractionated brain lysates showed that upstream autophagosomal proteins were detected in the soluble and insoluble fraction in DLB, corresponding to the bands of phosphorylated α‐synuclein. However, Western blot analysis of total brain lysates in PD and DLB showed that the increase of upstream autophagosomal proteins was only partial. The quantitative, qualitative and locational alteration of upstream autophagosomal proteins in the present study indicates their involvement in the pathogenesis of LB disease. Our data also suggest that misinduction or impairment of upstream autophagy might occur in the disease process of LB disease.     

Decreased oligodendrocyte nuclear diameter in Alzheimer's disease and lewy body dementia

To better understand the pathogenesis of dementia, it is important to understand histopathologic changes in neurodegenerative diseases because they might highlight key aspects of the degenerative process. In this study, the nuclear diameter of neurons and oligodendrocytes in selected temporal lobe areas were determined in autopsy tissue sections from patients with Alzheimer's disease (AD), Lewy body dementia (LBD) and controls. Our morphometric studies targeted neurons in the CA4 region of the pyramidal cell layer of the hippocampus, neurons in the granular layer of the dentate gyrus and oligodendrocytes in parahippocampal white matter. Mean neuronal nuclear diameters were not different among the studied groups. However, our studies revealed a statistically significant reduction of mean oligodendrocyte nuclear diameter in AD and LBD relative to controls. The reduction of the mean nucleus diameter of oligodendrocytes in LBD was independent of the presence of associated AD pathology in LBD. These findings for the first time identify decreased oligodendrocyte nucleus diameter as a morphologic feature of AD and LBD and may lead to a better understanding of the role of oligodendrocytes in AD and LBD pathogenesis.     

Diagnostic performance of a CSF-biomarker panel in autopsy-confirmed dementia

To establish diagnostic performance of the cerebrospinal fluid (CSF) biomarkers β-amyloid peptide (Aβ_1–42), total tau-protein (T-tau) and tau phosphorylated at threonine 181 (P-tau_181P) compared to clinical diagnosis, biomarker levels were determined in CSF samples from 100 autopsy-confirmed dementia and 100 control subjects. As the control and dementia groups were not age-matched and given the significant associations of biomarker concentrations with age in controls, age-corrected biomarker concentrations were calculated.New models were constructed by means of logistic regression. Using all biomarkers, dementia could be discriminated from controls (sensitivity (S) = 86%, specificity (Sp) = 89%). T-tau and Aβ_1–42 optimally discriminated Alzheimer's disease (AD) from other dementias (NONAD) and controls (S = 90%, Sp = 89%). AD was optimally discriminated from NONAD using P-tau_181P and Aβ_1–42 (S = 80%, Sp = 93%). Diagnostic accuracy of the latter model (82.7%) was comparable to clinical diagnostic accuracy (81.6%) that was based on a whole clinical work-up (including imaging). Using this model, in cases with clinically doubtful diagnoses, a correct diagnosis would have been established in 4/6 autopsy-confirmed AD and 3/3 autopsy-confirmed NONAD cases.The value of biomarkers in differential dementia diagnosis was shown, using pathological diagnosis as a reference. New models have been developed, achieving sensitivity, specificity and diagnostic accuracy levels, consistently exceeding 80%.     

Correlation in Lewy pathology between the claustrum and visual areas in brains of dementia with Lewy bodies

We investigated Lewy pathologies in the claustrum and the related cerebral cortices and subcortical nuclei of dementia with Lewy bodies (DLB) brains using alpha-synuclein-immunohistochemistry to clarify the relationship between Lewy pathology in the claustrum and visual misidentification of DLB patients. The claustrum is known to have strong reciprocal connections with the visual areas. Consequently, the claustrum demonstrated many Lewy bodies (LB) and LB-related neurites. The insular and inferior temporal cortices, amygdala, BA 18, 19, transentohrinal and cingulate cortices showed stronger or similar Lewy pathology as compared with the claustrum, while BA 17, precentral, postcentral and transverse temporal cortices showed weaker Lewy pathology. Comparing the correlation coefficient of Lewy pathology between the clausturm and other regions, BA 18 and 19 as well as the insular and transentorhinal cortices demonstrated a higher correlation coefficient. These findings suggest that Lewy pathology in the claustrum is more closely associated with that in visual areas than in auditory, somatosensory or motor areas, and that dysfunction of the visuo-claustral pathway participates in visual misidentification in addition to the visuo-amygdaloid pathway. The paralimbic cortices including the insular and transentorhinal cortices may connect visual areas with limbic areas by relay of the visuo-claustral or visuo-amygdaloid pathway.     

Neuritic plaques in the Lewy body variant of Alzheimer disease lack paired helical filaments

The Lewy body variant of Alzheimer disease (LBV) is a distinct category of dementia which, unlike pure diffuse Lewy body disease (DLBD), meets clinical and neuropathologic criteria for Alzheimer disease (AD) but differs from pure AD in having a neocortical predominance of diffuse and neuritic plaques (NP), with very few neurofibrillary tangles (NFT). We investigated the immunoreactivity of NP with a monoclonal antibody against paired helical filaments (PHF) composed of phosphorylated microtubule associated protein tau. With routine thioflavin-S preparations, 12 LBV and 14 AD cases had similar numbers of NP, but the LBV had significantly (P<0.05) fewer NFT per microscopic field in the midfrontal cortex. Among subjects with midfrontal NFT, 81–84% of NP in AD and LBV were anti-PHF positive. Among subjects without midfrontal NFT, 52% of NP in AD but only 12% of NP in LBV cases were anti-PHF positive (P<0.05). LBV differs from AD in that its NP generally do not contain PHF, unless they are accompanied by neocortical NFT.     

The presence of tau distinguishes Lewy bodies of diffuse Lewy body disease from those of idiopathic Parkinson disease

The antigenic components of Lewy bodies in the cerebral cortex and substantia nigra in 5 cases of diffuse Lewy body disease were examined by immunocytochemistry, using antibodies to neurofilaments (in the phosphorylated or non-phosphorylated forms); to ubiquitin; to the microtubule-associated proteins MAP1, MAP2 and tau; to isolated Alzheimer paired helical filaments, and to tubulin, in the tyrosinated and non-tyrosinated forms. Immunoreactivity with antibodies to cytoskeletal components was identical to that previously described for Lewy bodies of idiopathic Parkinson disease, with the exception that the inclusions of diffuse Lewy body disease (in both cortex and substantia nigra) were stained by an antibody to tau protein. Our findings indicate that although the inclusions found in diffuse Lewy body disease share structural and epitopic features with the inclusions of idiopathic Parkinson disease, they also have distinguishing characteristics (in addition to the differing neuronal populations involved). Also, they suggest that although the inclusions in both conditions appear similar, they probably have different pathogenetic origins.