Neuropathologic substrates of Parkinson disease dementia

Accepted September 14, 1998. From the Neuropharmacology Unit, Defense and Veterans Head Injury Program, Henry M. Jackson Foundation, and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; Veterans Administration Medical Center GRECC, Bedford, Massachusetts; and Departments of Neurology and Pathology, Boston University Medical School, Boston, Massachusetts. Address correspondence to Dr. Litvan, Neuropharmacology Unit, Defense and Veterans Head Injury Program, Henry M. Jackson Foundation, NINDS, NIH, Federal Building, Room 714, 7550 Wisconsin Avenue, Bethesda, MD 20892-9130; e-mail: litvan1@helix.nih.gov Copyright q 1999 American Psychiatric Press, Inc. Clinicopathologic Case Report

The Role of NAC in Amyloidogenesis in Alzheimer's Disease

Dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and Parkinson’s disease (PD) collectively known as Lewy body diseases (LBDs) are neuropathologically characterised by α-synuclein deposits (Lewy bodies and Lewy neurites). However, LBDs also exhibit pathology associated with Alzheimer’s disease (AD) (i.e. hyperphosphorylated tau and amyloid β (Aβ). Aβ can be deposited in the walls of blood vessels in the brains of individuals with AD, termed cerebral amyloid angiopathy (CAA). The aim of this study was to investigate the type and distribution of CAA in DLB, PDD, and PD and determine if this differs from AD. CAA type, severity, and topographical distribution was assessed in 94 AD, 30 DLB, 17 PDD, and 11 PD cases, and APOE genotype evaluated in a subset of cases where available. 96.3% AD cases, 70% DLB cases and 82.4% PDD cases exhibited CAA (type 1 or type 2). However only 45.5% PD cases had CAA. Type 1 CAA accounted for 37.2% of AD cases, 10% of DLB cases, and 5.9% of PDD cases, and was not observed in PD cases. There was a hierarchical topographical distribution in regions affected by CAA where AD and DLB displayed the same distribution pattern that differed from PDD and PD. APOE ε4 was associated with severity of CAA in AD cases. Topographical patterns and severity of CAA in DLB more closely resembled AD rather than PDD, and as type 1 CAA is associated with clinical dementia in AD, further investigations are warranted into whether the increased presence of type 1 CAA in DLB compared to PDD are related to the onset of cognitive symptoms and is a distinguishing factor between LBDs. Possible alignment of the the topographical distribution of CAA and microbleeds in DLB warrants further investigation. CAA in DLB more closely resembles AD rather than PDD or PD, and should be taken into consideration when stratifying patients for clinical trials or designing disease modifying therapies.

Convergence of Heat Shock Protein 90 with Ubiquitin in Filamentous α-Synuclein Inclusions of α-Synucleinopathies

Mental and Behavioral Dysfunction in Movement Disorders

Progressive cognitive decline in combination with a cerebrospinal fluid biomarker pattern of low levels of amyloid-β1-42 and high levels of total tau and phosphorylated tau is typical of Alzheimer's disease. However, several neurodegenerative disorders may overlap with Alzheimer's disease both in regards to clinical symptoms and neuropathology. In a uniquely large cohort of dementia patients, we examined the associations of cerebrospinal fluid biomarkers for Alzheimer's disease molecular pathology with clinical dementia diagnoses and disease severity. We cross-referenced the Swedish Dementia Registry with the clinical laboratory database at the Sahlgrenska University Hospital. The final data set consisted of 5676 unique subjects with a clinical dementia diagnosis and a complete set of measurements for cerebrospinal fluid amyloid-β1-42, total tau and phosphorylated tau. In cluster analysis, disregarding clinical diagnosis, the optimal natural separation of this data set was into two clusters, with the majority of patients with early onset Alzheimer's disease (75%) and late onset Alzheimer's disease (73%) assigned to one cluster and the patients with vascular dementia (91%), frontotemporal dementia (94%), Parkinson's disease dementia (94%) and dementia with Lewy bodies (87%) to the other cluster. Frontotemporal dementia had the highest cerebrospinal fluid levels of amyloid-β1-42 and the lowest levels of total tau and phosphorylated tau. The highest levels of total tau and phosphorylated tau and the lowest levels of amyloid-β1-42 and amyloid-β1-42:phosphorylated tau ratios were found in Alzheimer's disease. Low amyloid-β1-42, high total tau and high phosphorylated tau correlated with low Mini-Mental State Examination scores in Alzheimer's disease. In Parkinson's disease dementia and vascular dementia low cerebrospinal fluid amyloid-β1-42 was associated with low Mini-Mental State Examination score. In the vascular dementia, frontotemporal dementia, dementia with Lewy bodies and Parkinson's disease dementia groups 53%, 34%, 67% and 53% of the subjects, respectively had abnormal amyloid-β1-42 levels, 41%, 41%, 28% and 28% had abnormal total tau levels, and 29%, 28%, 25% and 19% had abnormal phosphorylated tau levels. Cerebrospinal fluid biomarkers were strongly associated with specific clinical dementia diagnoses with Alzheimer's disease and frontotemporal dementia showing the greatest difference in biomarker levels. In addition, cerebrospinal fluid amyloid-β1-42, total tau, phosphorylated tau and the amyloid-β1-42:phosphorylated tau ratio all correlated with poor cognitive performance in Alzheimer's disease, as did cerebrospinal fluid amyloid-β1-42 in Parkinson's disease dementia and vascular dementia. The results support the use of cerebrospinal fluid biomarkers to differentiate between dementias in clinical practice, and to estimate disease severity.

The aim of our study is to analyze sex-specific patterns of Parkinson's disease dementia (PDD) incidence. We are investigating the extent to which sex differences in survival after initial Parkinson's disease (PD) diagnosis influence differences in PDD risk among PD patients. We used a random sample of German longitudinal health claims data of persons ages 50+ (2004-2019; n = 250,000) and identified new PD cases ages 65+ who were followed-up for a PDD diagnosis or death between 2006 and 2017. We performed Cox and competing-risk regression models, with death as competing event, to calculate PDD hazard ratios (HR) adjusted for age at PD onset, PD severity as measured by the modified Hoehn and Yahr (HY) scale, comorbidities, and medications. Of 2195 new PD cases, 602 people died before PDD and 750 people developed PDD by the end of 2017. The adjusted risk of PDD differs by sex, with men having a higher PDD risk than women. When accounting for death, men and women do not differ in their PDD risk (HR = 1.02, P = 0.770). Sex-specific analyses showed significant age and severity effects in women (age: HR = 1.05, P < 0.001; HY 3-5 vs. 0-2.5: HR = 1.46, P = 0.011), but not in men. Older age at first PD diagnosis and higher disease severity increase PDD risk, but this association is attenuated for PD men when controlling for death. This implies that the most frail PD men die rapidly before receiving a dementia diagnosis, whereas women with PD survive at higher rates, regardless of their age at onset and disease severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

This study investigated clinical and neuropathological differences between DLB and PDD. 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. CAA was more common in DLB than in PDD (P=0.003). The severity of CAA was greater in DLB than in PDD (P=0.009), with significantly higher CAA scores in the parietal lobe (P=0.043), and the occipital lobe (P=0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD.

Are there morphological differences between Parkinson's disease-dementia and dementia with Lewy bodies?

LRP10 in α-synucleinopathies

Lewy body dementia (LBD) and Parkinson's disease-dementia (PDD) are two major neurocognitive disorders with Lewy bodies (LB) of unknown etiology. There is considerable clinical and pathological overlap between these two conditions that are clinically distinguished based on the duration of Parkinsonism prior to development of dementia. Their morphology is characterized by a variable combination of LB and Alzheimer's disease (AD) pathologies. Cerebral amyloid angiopathy (CAA), very common in aged persons and particularly in AD, is increasingly recognized for its association with both pathologies and dementia. To investigate neuropathological differences between LB diseases with and without dementia, 110 PDD and 60 LBD cases were compared with 60 Parkinson's disease (PD) cases without dementia (PDND). The major demographic and neuropathological data were assessed retrospectively. PDD patients were significantly older than PDND ones (83.9 vs 77.8years; p < 0.05); the age of LB patients was in between both groups (mean 80.2years), while the duration of disease was LBD < PDD < PDND (mean 6.7 vs 12.5 and 14.3years). LBD patients had higher neuritic Braak stages (mean 5.1 vs 4.5 and 4.0, respectively), LB scores (mean 5.3 vs 4.2 and 4.0, respectively), and Thal amyloid phases (mean 4.1 vs 3.0 and 2.3, respectively) than the two other groups. CAA was more common in LBD than in the PDD and PDND groups (93 vs 50 and 21.7%, respectively). Its severity was significantly greater in LBD than in PDD and PDND (p < 0.01), involving mainly the occipital lobes. Moreover, striatal Aβ deposition highly differentiated LBD brains from PDD. Braak neurofibrillary tangle (NFT) stages, CAA, and less Thal Aβ phases were positively correlated with LB pathology (p < 0.05), which was significantly higher in LBD than in PDD < PDND. Survival analysis showed worse prognosis in LBD than in PDD (and PDND), which was linked to both increased Braak tau stages and more severe CAA. These and other recent studies imply the association of CAA-and both tau and LB pathologies-with cognitive decline and more rapid disease progression that distinguishes LBD from PDD (and PDND).

Dementia in parkinsonism is caused by a variety of central nervous system (CNS) lesions, of which the molecular and pathogenic causes are poorly understood but probably include: 1. Degeneration of subcortical ascending systems with neuronal losses in dopaminergic, noradrenergic, serotonergic, cholinergic or multiple systems including the amygdyloid nucleus; 2. limbic and/or cortical Alzheimer and/or Lewy body pathologies, with loss of synapses and neurons, and 3. a combination of these lesions or additional CNS pathologies. In general, degeneration of subcortical neuronal networks appears insufficient to induce severe mental decline although, occasionally, cognitive impairment occurs without apparent cortical lesions. On the other hand, neuritic cortical Alzheimer change showing similar or differential distribution compared to Alzheimer's disease (AD) displays a significant linear correlation with dementia in Parkinsonism. Plaques can be associated with cortical Lewy bodies and, the contribution of each to dementing processes remains unresolved. In a consecutive autopsy series of 610 patients with parkinsonism, the total prevalence of retrospectively assessed dementia was 34.6%. In Parkinson's disease (PD) of the Lewy body type, it was 30.2%, mostly associated with other brain lesions, mainly AD, while only 3.5% of "pure" PD without additional brain pathologies were demented. There was no significant difference in age and duration of illness between demented and non-demented PD patients. Secondary parkinsonian syndromes showed a higher incidence of dementia (56.3%), again with predominant Alzheimer pathology which was present in 73% of the total of demented parkinsonian patients and in almost 82% of the demented PD cases in this series. The specific contribution of cortical and subcortical lesions to mental impairment in parkinsonism, their relationship to AD, and an etiology await further elucidation.

Lewy body dementias are the second most common neurodegenerative dementias after Alzheimer's disease and include dementia with Lewy bodies and Parkinson's disease dementia. They share similar clinical and neuropathological features but differ in the time of dementia and parkinsonism onset. Although Lewy bodies are their main pathological hallmark, several studies have shown the emerging importance of Alzheimer's disease pathology. Clinical amyloid-β imaging using Pittsburgh Compound B (PiB) supports neuropathological studies which found that amyloid-β pathology is more common in dementia with Lewy bodies than in Parkinson's disease dementia. Nevertheless, other co-occurring pathologies, such as cerebral amyloid angiopathy, TDP-43 pathology and synaptic pathology may also influence the development of neurodegeneration and dementia. Recent genetic studies demonstrated an important role of APOE genotype and other genes such as GBA and SNCA which seem to be involved in the pathophysiology of Lewy body dementias. The aim of this article is to review the main clinical, neuropathological and genetic aspects of dementia with Lewy bodies and Parkinson's disease dementia. This is particularly relevant as future management for these two conditions may differ.

Le corps de Lewy, marqueur abusif de la maladie de Parkinson ?

Dementia is common in advanced Parkinson's disease (PD), especially in the elderly [2]. Cerebral white matter lesions (CWMLs) have been described in normal aging, vascular dementia (VD), and Alzheimer's disease (AD) [4, 5]. CWMLs may be associated with increased risk of dementia, disability, and death. Whether CWML burden in AD correlates with cognitive decline remains uncertain. Reports are scant on the influence of CWMLs in PD dementia (PDD). We reviewed medical records and autopsy findings of PD patients between 1990 and 2008 from the Sun Health Research Institute Brain and Body Donation Program. All cases reviewed had a complete neuropathological examination. Diagnosis of PD was based on UK brain bank criteria. DSM IV criteria for dementia were used. Previous studies have largely utilized ante-mortem neuroimaging quantification of white matter burden. Our study is the first to quantify CWMLs pathologically in PDD. Pathologically, gross and microscopic neuropathologic assessments were made by a single observer (TGB) without knowledge of the history or diagnosis. The clinical history was reviewed subsequently in order to make an appropriate clinicopathologic diagnosis. Diagnostic histological methods were performed on standard blocks of tissue fixed in 4% buffered formaldehyde and then either dehydrated and embedded in paraffin or cryoprotected and cut on a freezing, sliding microtome. Details of the methods have been previously published [1]. Neuropathological diagnoses were based on published consensus criteria. For AD, this required an NIA-Reagan “intermediate” or “high” probability [7]. For VD, the NINDS-AIREN criteria were used [6]. For progressive supranuclear palsy (PSP) and other relevant conditions, the histopathological methodologies described by Dickson [3] were employed. CWMLs were rated in the frontal, parietal, temporal, and occipital lobes as follows: grade 1 is restriction to the immediate periventricular area, occupying less than one-third of the centrum semiovale; grade 2 is involvement of one-third to two-thirds; while grade 3 is involvement of more than two-thirds of the centrum semiovale (Fig. 1). Fig. 1 H&E-stained thick (40 μ) formalin-fixed, frozen sections of the frontal lobe from eight different subjects with a clinicopathologic diagnosis of Parkinson's disease, illustrating the grading system used for cerebral white matter rarefaction. ... All subjects were confirmed to have the typical PD histopathology. Cases with concurrent pathology meeting criteria for AD, hippocampal sclerosis (HS), VD, and PSP were excluded. White matter scores were compared between PDD and PD cognitively normal (PD-CogNL) subjects. Mean levels were compared by using the paired t test. Prevalence was compared by using the McNemar test. Adjusted odds ratios were calculated by using multiple logistic regression modeling. Logistic regression was used because the distribution of white matter scores was skewed. Of 108 subjects who were diagnosed as PD, 54 patients had no concurrent HS, PSP, AD, or VD on pathology. Three were excluded because of a history of a brain tumor or severe head injury, yielding 26 PDD and 25 PD-CogNL (Table 1). The crude mean white matter score and the prevalence of positive white matter scores were not higher in the PDD group. However, the crude comparisons were confounded by age at death, age at the onset of PD, and duration of PD. After adjusting for these factors, the odds ratio for dementia versus positive white matter score was 2.6 (95% CI = 0.43–16). Given the large CI, further analysis was done. The sample indicates 73% probability (Bayes posterior with a non-informative prior) that the OR is greater than 1.5 and 85% probability that the OR is greater than 1.0. A sample of 75 subjects per group would have 80% power to detect an OR of 2.6 (α = 0.05, π0 = 0.50). Table 1 Comparison of 26 subjects with Parkinson's disease dementia (PDD) versus 25 non-demented individuals with Parkinson's disease (PD-CogNL) Our results tentatively support the hypothesis that the cumulative burden of CWMLs correlates with dementia in PD patients with no concurrent AD, HS, VD, or PSP. A sample three times larger would be needed in order to validate this finding with adequate power.