Cerebral amyloid angiopathy in Lewy body disease

Summary. While Alzheimer and Lewy body pathologies are discussed as major substrates of dementia in Parkinson’s disease (PD/Lewy body disease of brainstem type), the incidence and impact of cerebral amyloid angiopathy (CAA) and its association with cognitive decline in PD and dementia with Lewy bodies (DLB) are unknown. The severity of CAA and other Alzheimer lesions were assessed in 68 cases of autopsy-confirmed PD, 32 of them with dementia (PDD), and in 20 cases of DLB. PDD patients were significantly older than those without dementia (mean age 84.5 vs 77.6 years; p < 0.01), the age of DLB patients was in between both groups (mean 80.0 years), while duration of disease was DLB < PDD < PD (mean 6.5 vs 8.5 and 14.3 years). PDD patients had a significantly higher neuritic Braak stage (mean 4.2 vs 2.4, p < 0.01), significantly higher cortical amyloid β (Aβ) load, capillary cerebral amyloid angiopathy (CapCAA) and generalized CAA than those without dementia (mild CapCAA in 22% vs moderate to severe CapCAA in 87%; mild generalized CAA in 5.5% vs moderate to severe generalized CAA in 82%). Mean PD stage was higher in both DLB and PDD than in PD (mean 5.2 vs 4.5 and 4.0, respectively): Mean neuritic Braak stage in DLB was 3.4, severe Aβ plaque load was seen in 95%, moderate to severe CapCAA in 90% and mild to severe generalized CAA in 70%. This and other recent studies imply an association of CAA with cognitive decline in both PD/PDD and DLB, particularly in cases with concomitant AD-type pathology. Correspondence: Kurt A. Jellinger, Institute of Clinical Neurobiology, Kenyongasse 18, 1070 Vienna, Austria     

Concomitant pathologies among a spectrum of parkinsonian disorders

IntroductionMany clinicopathological studies do not specify the presence of other pathologies located within the brain, so disease heterogeneity may be under appreciated.ObjectiveThe purpose of this study was to determine the frequencies of concomitant pathologies among parkinsonian disorders.MethodsData from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), an ongoing longitudinal clinical-neuropathological study, was used to analyze concomitant pathologies, including Alzheimer's disease (AD), argyrophilic grains (Arg), cerebral amyloid angiopathy (CAA), cerebral white matter rarefaction (CWMR) and overlap of each parkinsonian disorder in clinico-pathologically defined Parkinson's disease (PD; N = 140), dementia with Lewy bodies (DLB; N = 90), progressive supranuclear palsy (PSP; N = 64), multiple system atrophy (MSA; N = 6), corticobasal degeneration (CBD; N = 7); and normal elderly (controls; N = 166).ResultsOf the neuropathologically-confirmed PD cases, 38% had a concomitant diagnosis of AD, 9% PSP, 25% Arg, 44% CWMR, and 24% CAA. For DLB, 89% had AD, 1% PSP, 21% Arg, 51% CWMR, and 50% CAA. For PSP cases, 36% had AD, 20% PD, 1% DLB, 44% Arg, 52% CWMR and 25% CAA. Similar heterogeneity was seen for MSA and CBD cases. Many cases had more than one of the above additional diagnoses.ConclusionsThese data demonstrate a great deal of concomitant pathologies among different types of parkinsonian disorders; this may help explain the heterogeneity of clinical findings.     

DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers

For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.     

Striatal Aβ peptide deposition mirrors dementia and differentiates DLB and PDD from other parkinsonian syndromes

Recent neuropathological studies have described widespread amyloid-β peptide (Aβ) deposition in the striatum of patients with Lewy body disorders, particularly in Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). However, positron emission tomography (PET) studies using the [(11)C]PIB ligand, binding to Aβ deposits, detects significant striatal pathology only in DLB and not in PDD. Employing immunohistochemistry, we examined striatal Aβ deposition in the caudate nucleus and putamen of 52 PD, 41 PDD, 14 DLB, 7 multiple system atrophy (MSA) and 14 progressive supranuclear palsy (PSP) cases in relation to the presence of dementia. PD, MSA and PSP cases showed little or no Aβ pathology in the striatum. In contrast, both PDD and DLB cases demonstrated significantly greater Aβ deposition in the striatum when compared to PD, MSA and PSP groups. We conclude that striatal Aβ pathology is common in both PDD and DLB and may reflect the development of dementia in these conditions. More detailed examination of the morphology of the Aβ pathology suggests that it is the presence of cored amyloid plaques in DLB, but not PDD, that underlies the differences seen in PET imaging.     

REM and NREM sleep enactment behaviors in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies

Background/objectiveNocturnal sleep enactment behaviors (SEBs) are common in patients affected by Parkinson’s disease (PD), dementia associated with Parkinson’s disease (PDD), and dementia with Lewy bodies (DLB). We investigated the occurrence and neurobiological significance of abnormal SEBs in the context of PD without cognitive decline compared to PDD/DLB patients.MethodsWe evaluated a sample of 139 patients with PD, PDD, or DLB in a cross-sectional survey. One hundred and seventeen patients showing either no cognitive impairment (PD group) or meeting the diagnostic requirements for dementia (PDD/DLB group) underwent video-polysomnography. Seventy subjects (42 males) in whom a clear-cut diagnosis of abnormal sleep-related motor-behavioral episodes was possible were included in the final analysis.ResultsSEBs consisting of RBD or occurring on arousal from NREM or REM sleep were globally more frequent in the dementia group (PDD/DLB) than in the PD group (p = 0.001), the difference being statistically significant for arousal-related episodes (p = 0.002), while a trend emerged for RBD (p = 0.07). Male sex, daytime sleepiness, higher motor impairment, and lower mini-mental score were significantly more frequent with the occurrence of abnormal sleep-related motor-behavioral episodes.ConclusionSEBs in PD, PDD, and DLB may consist of RBD episodes or of arousal-related NREM and REM episodes. These latter are more frequent in patients with PDD/DLB and seem to be mainly related to more advanced stages of disease with a higher degree of cognitive decline.     

Cortical Lewy body pathology in the diagnosis of dementia

Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are distinguishable clinically but often not neuropathologically. This study aims to test whether the distribution of cortical Lewy bodies differs in these clinicopathological groups and to develop diagnostic protocols for their differentiation. Brains were obtained at autopsy from cases recruited from prospective clinical studies of dementia or movement disorders. All cases with significant pathologies other than Lewy bodies or plaques were excluded. Cases were categorised into either PD without dementia, DLB (dementia first or within 2 years of disease onset), or PD with a later onset of dementia (PDD). The distribution and density of Lewy bodies and Lewy neurites was determined using antibodies to ubiquitin and alpha-synuclein. Cortical Lewy body densities could not separate cases of DLB from those with PDD. However, semiquantitative thresholds in the parahippocampus could separate demented from non-demented cases with high sensitivity and specificity. Interactions between multiple pathologies were determined using factor analysis. Although many cases had CA2 Lewy neurites, this was not associated with severity or duration of either dementia or parkinsonism. Most DLB cases had significant plaque pathology, and severity and duration of dementia was related to both increasing parahippocampal Lewy body densities and neuritic plaque grade. Weighted kappa statistics revealed that the combination of these pathologies indicated a more severe dementia. These results suggest that dual pathologies cause DLB, and high densities of parahippocampal Lewy bodies indicate dementia regardless of additional pathologies.     

Neuroleptic sensitivity in Parkinson's disease and parkinsonian dementias

BACKGROUND: Severe sensitivity to neuroleptic agents is a major clinical problem in dementia with Lewy bodies (DLB), but has not been determined in Parkinson's disease (PD) and PD with dementia (PDD). METHOD: Severe neuroleptic sensitivity reactions (NSRs) were evaluated according to an operationalized definition blind to clinical and neuropathologic diagnoses in prospectively studied patients exposed to neuroleptics from 2 centers. The study was conducted from June 1995 to May 2003. RESULTS: Ninety-four patients were included (15 with DLB, 36 with PDD, 26 with PD, 17 with Alzheimer's disease, all diagnosed with various operational criteria). Severe NSR only occurred in patients with Lewy body disease: DLB (8 [53%]), PDD (14 [39%]), and PD (7 [27%]), but did not occur in Alzheimer's disease (p = .006). Severe NSR was not associated with other clinical or demographic features. In DLB, severe NSR was not associated with neuropathologic indices (Consortium to Establish a Registry for Alzheimer's Disease staging, Braak staging, or cortical distribution of Lewy bodies). CONCLUSIONS: An operationalized evaluation of severe NSR blind to diagnosis confirmed the high prevalence in DLB and identified high frequencies in Parkinson's disease and PDD with important implications for clinical practice.     

Prevalence and clinical associations of tau in Lewy body dementias: A systematic review and meta-analysis

IntroductionAlzheimer's disease neuropathologies (amyloid-β and tau) frequently co-exist to varying degrees in Lewy body dementias (LBD), which include dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).ObjectivesTo investigate the prevalence of tau in DLB and PDD, and its associations with clinical outcomes.MethodsWe searched the major electronic databases using the search term: (“dementia with Lewy bodies” OR “diffuse Lewy body disease” OR “Lewy body variant of Alzheimer's disease”) AND (“tau protein” OR “tauopathy” OR “neurofibrillary tangle”), for relevant studies which evaluated tau in LBD. Forty-nine articles met the inclusion criteria for data extraction. Where appropriate, a random-effect meta-analysis was performed to obtain pooled estimates for prevalence and risk ratios (RR) or standardized mean differences (SMD) for clinical features, diagnostic accuracy and cognition.ResultsBraak neurofibrillary tangle stage ≥ III was observed in 66% (n = 1511, 95%CI 60%–73%) of DLB and 52% (n = 433, 95%CI 27%–76%) of PDD at autopsy. Abnormal CSF phosphorylated-tau levels were present in 28% (n = 925, 95%CI 25%–31%) of DLB and 15% (n = 172, 95%CI 5%–24%) of PDD cases. Higher tau burden in DLB was associated with reduced likelihood of manifesting visual hallucinations (RR 0.56; 95%CI 0.40–0.77) and motor parkinsonism (RR 0.62; 95%CI 0.40–0.98), lower diagnostic accuracy of DLB during life (RR 0.49; 95%CI 0.38–0.64) and worse cognition prior to death (SMD 0.63; 95%CI 0.46–0.81).ConclusionsTau is common in LBD and may reduce clinical diagnostic accuracy in people with DLB. Prospective longitudinal studies are needed to understand the roles of co-morbid neuropathologies in Lewy body dementias.     

Sonographic discrimination of dementia with Lewy bodies and Parkinson's disease with dementia

Objective To study the use of transcranial sonography (TCS) in discriminating between patients with dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). Methods Fourteen patients with DLB, 31 with PDD and 73 with PD without dementia (PDnD) were studied with TCS. Results All assessable patients with DLB, 97% with PDD, and 94% with PDnD showed at least unilateral hyperechogenicity of substantia nigra (SN). However, bilateral marked SN hyperechogenicity was present in 80% of DLB patients but only in one third of PDD and PDnD patients, and was associated with younger age at disease onset in PD but not in DLB. An asymmetry index ≥ 1.15 of bilateral SN echogenic sizes, estimated by division of larger size by smaller size, was found in 69% of PDD patients but only 20% of DLB patients. Combination of SN echogenic sizes, asymmetry indices and onset age discriminated PDD from DLB with a sensitivity of 96%, a specificity of 80% and a positive predictive value of 93%. TCS of brainstem raphe, thalami, lenticular nuclei, caudate nuclei and ventricle widths did not discriminate between DLB and PDD. Compared with PDnD patients, DLB and PDD patients exhibited significantly larger widths of third ventricle and of frontal horns. In PDD patients, scores on the Unified Parkinson's Disease Rating Scale correlated with widths of third ventricle and of frontal horns. Conclusions SN hyperechogenicity is typical for PDD and DLB.However, size, asymmetry and relation of SN hyperechogenicity to age at disease onset discriminate PDD from DLB.     

Extrapyramidal features in Parkinson's disease with and without dementia and dementia with Lewy bodies: A cross-sectional comparative study.

Risk factors predicting an increased risk of dementia in Parkinson's disease (PD) are not fully established. The dementia associated with PD (PDD) closely resembles dementia with Lewy bodies (DLB). Based upon a high frequency of non-dopaminergic mediated clinical features in DLB, we predicted that a motor subtype comprising postural instability and balance problems would be more common in PDD. We examined extrapyramidal, cognitive, and affective features in 38 PD, 43 PDD, and 26 DLB patients in a cross-sectional study design. Motor subtype was subdivided into postural-instability gait difficulty (PIGD) or tremor (TD) dominant. The PIGD-subtype was more common in PDD (88% of cases) and DLB (69% of cases) groups compared with the PD group (38% of cases), in which TD and PIGD sub-types were more equally represented (P < 0.001). Although the mean depression scores overall were modest, PDD patients scored significantly higher than PD, but not DLB patients (Cornell; P = 0.006, and Geriatric Depression scale, GDS-15; P = 0.001), while within the PD group, those patients with a PIGD subtype had greater depression scores than the TD subtype (GDS-15; P < 0.05). We conclude that non-dopaminergic motor features are frequent in PDD. Neurodegeneration within the cholinergic system is likely to mediate many of these motor problems, as well as playing a significant role in determining the neuropsychiatric symptomatology of both PDD and DLB.     

Molecular Imaging and Updated Diagnostic Criteria in Lewy Body Dementias

Purpose of Review

The aims of the study were to review recent advances in molecular imaging in the Lewy body dementias (LBD) and determine if these may support the clinical but contested temporal profile distinction between Parkinson disease (PD) with dementia (PDD) versus dementia with Lewy bodies (DLB).

Recent Findings

There do not appear to be major regional cerebral metabolic or neurotransmitter distinctions between PDD and DLB. However, recent studies highlight the relative discriminating roles of Alzheimer proteinopathies. PDD patients have lower cortical β-amyloid deposition than DLB. Preliminary tau PET studies suggest a gradient of increasing tau binding from cognitively normal PD (absent to lowest) to cognitively impaired PD (low) to DLB (intermediate) to Alzheimer disease (AD; highest). However, tau binding in DLB, including the medial temporal lobe, is substantially lower than in AD.

Summary

Alzheimer-type proteinopathies appear to be more common in DLB compared to PDD with relative but no absolute differences. Given the spectrum of overlapping pathologies, future α-synuclein ligands are expected to have the best potential to distinguish the LBD from pure AD.

     

Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease

Whereas the prevalence and impact of vascular pathology in Alzheimer diease (AD) are well established, the role of vascular and Alzheimer pathologies in the progression of neurodegeneration and cognitive impairment in Parkinson disease (PD) is under discussion. A retrospective clinico-pathologic study of 100 patients with autopsy proven PD (including 44 cases with dementia/PDD) and 20 cases of dementia with Lewy bodies (DLB) confirmed essential clinical (duration of illness, Mini-Mental State Examination/MMSE, age at death) and morphologic differences between these groups; Lewy body Braak scores and Alzheimer pathologies (neuritic Braak stage, cortical Aβ plaque load, and generalized cerebral amyloid angiopathy or CAA) were significantly higher/more severe in DLB and PDD than in PD without dementia. Duration of illness showed no association to any of the examined pathologic parameters, while there was a moderate association between LB scores and neuritic Braak stages, the latter significantly increasing with age. Significant association between cerebrovascular lesions and neuritic Braak stage was seen in PDD but not in PD subjects without dementia. These data suggest an influence of Alzheimer-related lesions on the progression of the neurodegenerative process and, in particular, on cognitive decline in both PDD and DLB. On the other hand, both these factors in PD and DLB appear to be largely independent from coexistent vascular pathology, except in cases with severe cerebrovascular lesions or those related to neuritic AD pathology. Assessment of ApoE genotype in a small number of cases showed no significant differences in the severity of Aβ plaque load and CAA except for much lower intensities in non-demented ε3/3 patients. Despite increasing evidence suggesting synergistic reactions between α-synuclein (αSyn), tau and Aβ-peptides, the major protein markers of both AD and Lewy body diseases, and of both vascular pathology and AD, the molecular background and pathophysiological impact of these pathologies on the progression of neurodegeneration and development of cognitive decline in PD await further elucidation. Dedicated to the memory of Professor Dr. Franz Seitelberger, a pioneer of modern neuropathology and neurosciences.     

Biochemical and pathological correlates of cognitive and behavioural change in DLB/PDD

Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are second only to Alzheimer’s disease (AD) in frequency. In particular it is evident that up to 80% of people with PD will develop dementia towards the end of their life. While the neurobiology of movement disorder has been well studied in PD, much less attention has been given to mechanisms underlying the cognitive and behavioural symptoms associated with DLB and PDD. To date, the best correlate of cognitive impairment appears to be cortical Lewy bodies; however, new emphasis has been placed on small aggregates of synuclein. Furthermore, very few studies have attempted to investigate the neurochemical correlates of behavioural disorders in DLB/PDD and whether these are similar or distinct from AD. Aggregated α-synuclein forms the core component of Lewy bodies, a major pathological feature of Parkinson’s-related conditions. The 26S proteasome is an ATP-dependent protease that catalyses the breakdown of α-synuclein. Previous studies have implicated alterations in the proteasome in PD. Furthermore, proteasome inhibitors have been reported to induce α-synuclein aggregation and Lewy body-like inclusions, resulting in neuronal loss both in vitro and in vivo. Our preliminary results indicate that selective alterations in the expression of proteosome sub-units are a feature of both DLB and PDD, while changes in activity are restricted to PDD. Depression is a common symptom in DLB/PDD, yet the evidence base for standard treatment with SSRIs is limited. In contrast to previous studies of AD, our results indicate that there is no association between depression and the 5-HT transporter, while there was a significant increase in the number of 5-HT1A receptors in those DLB/PDD patients with depression. These data may provide an insight into the lack of success of current treatments and suggest alternative approaches.

     

Clinical evaluation of Parkinson's disease dementia: association with aging and visual hallucination

OBJECTIVES: In order to explore factors associated with the development of dementia in Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), we systematically investigated the clinical evaluation of PD and DLB patients hospitalized in the Department of Neurology at Tottori University Hospital, Japan. RESULTS: There were 208 patients diagnosed as having PD and 39 patients diagnosed with DLB in this study. Of the patients with PD, 67 (32%) developed dementia and only five PD+ patients were considered to have cognitive impairment attributable to Alzheimer's disease (AD) or vascular dementia (VaD). Fifty-four (81%) PDD patients had visual hallucinations (VH) with or without cognitive fluctuation. The onset age of parkinsonian motor symptoms of patients with PD dementia (PDD) did not differ from that of PD patients without dementia. There was a significant inverse correlation between the onset age of motor symptoms in PD and the onset of their dementia in PDD. Seventy-five (36%) patients with PD had experienced VH and most of the PDD patients had experienced VH within 1 year before or after diagnosis of PDD. CONCLUSIONS: These results indicate that aging and VH are important factors associated with dementia in PD.     

Review: The spectrum of clinical features seen with alpha synuclein pathology

It has been recognized for many years that a number of chronic neurodegenerative diseases of the CNS are characterized by the development of intracellular inclusion bodies, but it is only relatively recently that the core proteins defining these pathologies have been defined. One such protein is alpha synuclein, that was found to be the main component of Lewy bodies in the late 1990s, and this discovery reinforced the emerging view that alpha synuclein was intimately linked to diseases characterized by this type of pathology – namely Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Furthermore at around this time, this same protein was also found within the glial inclusion bodies of patients dying with multiple system atrophy (MSA). These three disorders constitute the majority of patients with an ‘alpha synucleinopathy’, although there are a number of rarer conditions that can also cause this pathology including inherited metabolic disorders such as Gaucher's disease (GD). In this review, we will concentrate on PD, the commonest alpha synucleinopathy, and its associated dementia (PDD), as well as discussing DLB and MSA and will highlight how the clinical features of these conditions vary as a function of pathology.     

A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson's disease with and without dementia

OBJECTIVES: To compare the frequency and clinical correlates of neuropsychiatric symptoms in patients with Parkinson's disease (PD) with and without dementia and in those with dementia with Lewy bodies (DLB). METHODS: Neuropsychiatric symptoms during the month prior to assessment were assessed in clinically diagnosed PD patients with dementia (PDD; n = 48) and without dementia (PDND; n = 83) and in 98 DLB patients (33% autopsy confirmed) using standardized instruments. RESULTS: Delusions and hallucinations were significantly more common in DLB (57% and 76%) than PDD (29% and 54%) and PDND (7% and 14%) patients (p < 0.001). In all groups, auditory and visual hallucinations and paranoid and phantom boarder delusions were the most common psychotic symptoms. Frequency of major depression and less than major depression did not differ significantly between the three groups. Clinical correlates of hallucinations in PD were dementia (odds ratio (OR) = 3.9; 95% confidence interval (CI) 1.5-10.4) and Hoehn-Yahr stage 3 or more (OR 3.4; 95% CI 1.0-12.0), whereas no significant clinical correlates of hallucinations were found in DLB patients. CONCLUSIONS: Delusions and hallucinations occur with increasing frequency in PDND, PDD and DLB patients, but the presentation of these symptoms is similar. These findings support the hypothesis that psychiatric symptoms are associated with cortical Lewy bodies or cholinergic deficits in the two disorders.     

Relationship between Parkinson disease with dementia and dementia with Lewy bodies

Parkinson disease (PD) and dementia with Lewy bodies (DLB) are considered Lewy body diseases (LBDs). To clarify the relation between PD with dementia (PDD) and DLB, 30 patients with LBD were divided into pathological subtypes according to the consensus guidelines for DLB. Patients with PDD showed neocortical and limbic type of LBD as well as patients with DLB. Dementia had not been noted in 2 patients with neocortical type. Our results indicate that PDD and DLB share a common pathological substrate and that the pathological subtypes of LBD show considerable overlap in clinical manifestations.     

Nigral Pathology Contributes to Microstructural Integrity of Striatal and Frontal Tracts in Parkinson's Disease

Background

Motor and cognitive impairment in Parkinson's disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant α-synuclein accumulation. Diffusion magnetic resonance imaging (MRI) can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood.

Objective

To unravel the pathological substrate(s) underlying microstructural alterations of SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD.

Methods

Combining post-mortem in situ MRI and histopathology, T1-weighted and diffusion MRI, and neuropathological samples of nine PD, six PD with dementia (PDD), five dementia with Lewy bodies (DLB), and 10 control donors were collected. From diffusion MRI, mean diffusivity (MD) and fractional anisotropy (FA) were derived from the SN, and tracts between the SN and caudate nucleus, putamen, and DLPFC. Phosphorylated-Ser129-α-synuclein and tyrosine hydroxylase immunohistochemistry was included to quantify nigral Lewy pathology and dopaminergic degeneration, respectively.

Results

Compared to controls, PD and PDD/DLB showed increased MD of the SN and SN-DLPFC tract, as well as increased FA of the SN-caudate nucleus tract. Both PD and PDD/DLB showed nigral Lewy pathology and dopaminergic loss compared to controls. Increased MD of the SN and FA of SN-caudate nucleus tract were associated with SN dopaminergic loss. Whereas increased MD of the SN-DLPFC tract was associated with increased SN Lewy neurite load.

Conclusions

In PD and PDD/DLB, diffusion MRI captures microstructural alterations of the SN and tracts to the dorsal striatum and DLPFC, which differentially associates with SN dopaminergic degeneration and Lewy neurite pathology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Cognitive profiles of individual patients with Parkinson's disease and dementia: comparison with dementia with lewy bodies and Alzheimer's disease.

We describe the pattern of cognitive profiles within a community-based sample of patients with Parkinson's disease (PD) and dementia (PDD) using cluster analyses, and compare the results with data from patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Fifty patients with PDD and 39 with AD from Stavanger, Norway, and 62 patients with DLB from San Diego, CA, USA were diagnosed by either standardized clinical procedures or criteria (all PDD and all AD cases) or necropsy (all DLB cases). Four subgroups were identified: two subgroups with a subcortical cognitive profile (one with mild and one with moderate dementia severity), one subgroup with global impairment and severe dementia, and one subgroup with a cortical cognitive profile and moderate dementia. Of the patients with PDD and with DLB, 56% and 55%, respectively, had a subcortical cognitive profile, compared with only 33% of the AD patients. Conversely, 30% of the patients with PDD and 26% of those with DLB had a cortical cognitive profile, compared with 67% of the patients with AD. These findings suggest that in some patients with PDD, frontosubcortical changes are the main contributing factor to dementia, whereas in other patients, cortical and hippocampal changes are more important.     

β‐amyloid in lewy body disease is related to Alzheimer's disease‐like atrophy

The aim of this study was to investigate whether amyloid deposition is associated with Alzheimer's disease (AD)‐like cortical atrophy in Lewy body (LB) disease (LBD). Participants included 15 LBD with dementia patients (8 with dementia with Lewy bodies [DLB] and 7 with Parkinson's disease [PD] with dementia [PDD]), 13 AD patients, and 17 healthy controls. Age, gender, and Mini–Mental State Examination scores were matched between patient groups. All subjects underwent PET scans with [¹¹C]Pittsburgh Compound B to measure brain amyloid deposition as well as three‐dimensional T1‐weighted MRI. Gray‐matter volumes (GMVs) were estimated by voxel‐based morphometry. Volumes‐of‐interest analyses were also performed. Forty percent of the 15 DLB/PDD patients were amyloid positive, whereas all AD patients and none of the healthy controls were amyloid positive. Amyloid‐positive DLB/PDD and AD patients showed very similar patterns of cortical atrophy in the parahippocampal area and lateral temporal and parietal cortices, with 95.2% of cortical atrophy distribution being overlapped. In contrast, amyloid‐negative DLB/PDD patients had no significant cortical atrophy. Compared to healthy controls, parahippocampal GMVs were reduced by 26% in both the amyloid‐positive DLB/PDD and AD groups and by 10% in the amyloid‐negative DLB/PDD group. The results suggest that amyloid deposition is associated with AD‐like atrophy in DLB/PDD patients. Early intervention against amyloid may prevent or delay AD‐like atrophy in DLB/PDD patients with amyloid deposition. © 2012 Movement Disorder Society