CSF diagnosis of Alzheimer’s disease and dementia with Lewy bodies

Summary. Differential diagnosis of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) is often crucial. CSF Tau protein and Amyloid-beta (Aβ) peptides have shown diagnostic value for the diagnosis of AD, but discrimination from DLB was poor. Herein, we investigate CSF of 18 patients with probable AD, 25 with probable DLB and 14 non-demented disease controls (NDC) by Aβ-SDS-PAGE/immunoblot and commercially available ELISAs for Aβ1-42 and tau. CSF Aβ peptide patterns and tau exhibited disease specific alterations among AD and DLB. The ratio of Aβ1-42 to Aβ1-38 and Aβ1-42 to Aβ1-37, respectively, in combination with absolute tau, yielded a sensitivity and specificity of 100 and 92%, respectively. We conclude that CSF Aβ peptide patterns and tau levels reflect disease-specific pathophysiological pathways of these dementias as distinct neurochemical phenotypes. Combined evaluation of these biomarkers provides a reasonable accuracy for differential diagnosis of AD and DLB.     

Motor cortex inhibitory circuits in dementia with Lewy bodies and in Alzheimer’s disease

Summary. To determine whether a peculiar neurophysiological profile may contribute to characterize dementia with Lewy bodies (DLB) vs. Alzheimer disease (AD), we used transcranial magnetic stimulation to examine the excitability of two different inhibitory systems of the motor cortex, short latency intracortical inhibition (SICI) and short latency afferent inhibition (SAI) in 10 patients with DLB, in 13 patients with AD and in 15 healthy subjects. SICI and SAI were significantly reduced in AD patients, while both were not significantly different from the controls in DLB patients. The differential pattern of SICI and SAI exhibited by AD vs. DLB may have diagnostic significance in discriminating DLB from AD. Furthermore, this technique may help to clarify the pathophysiological entity of DLB; since SAI is a cortical phenomenon that depends on central cholinergic activity, our findings suggest that the mechanisms of cholinergic depletion in DLB may be different from that in AD, while normal SICI may reflect a less pronounced dysregulation of the intracortical GABAergic inhibitory circuitries in DLB.     

Eyelid retraction in dementia with Lewy bodies and Parkinson’s disease

Journal of Neurology -     

Atrophy of the cholinergic basal forebrain in dementia with Lewy bodies and Alzheimer’s disease dementia

Similar to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) is characterized by a profound degeneration of cortically-projecting cholinergic neurons of the basal forebrain (BF) and associated depletion of cortical cholinergic activity. We aimed to investigate subregional atrophy of the BF in DLB in vivo and compare it to the pattern of BF atrophy in AD. Structural MRI scans of 11 patients with DLB, 11 patients with Alzheimer’s disease, and 22 healthy controls were analysed using a recently developed technique for automated BF morphometry based on high-dimensional image warping and cytoarchitectonic maps of BF cholinergic nuclei. For comparison, hippocampus volume was assessed within the same morphometric framework using recently published consensus criteria for the definition of hippocampus outlines on MRI. The DLB group demonstrated pronounced and subregion-specific atrophy of the BF which was comparable to BF atrophy in AD: volume of the nucleus basalis Meynert was significantly reduced by 20–25 %, whereas rostral BF nuclei were only marginally affected. By contrast, hippocampus volume was markedly less affected in DLB compared to AD. Global cognition as determined by MMSE score was associated with BF volume in AD, but not in DLB, whereas visuoperceptual function as determined by the trail making test was associated with BF volume in DLB, but not in AD. DLB may be characterized by a more selective degeneration of the cholinergic BF compared to AD, which may be related to the differential cognitive profiles in both conditions.     

Follow-up investigations in cerebrospinal fluid of patients with dementia with Lewy bodies and Alzheimer’s disease

Summary. Measuring proteins in cerebrospinal fluid (CSF) has gained wide acceptance for the differential diagnosis of dementia. Some groups have already extended these investigations in Alzheimers disease (AD) by asking how stable these markers are in follow-up analysis, if they depend on the stage of disease and whether they can be used to monitor the progression and biological effects of treatment. We evaluated 21 patients with dementia with Lewy bodies (DLB) and 19 patients with AD, on two occasions, with regard to levels of tau protein, tau protein phosphorylated at threonine 181 (p-tau), A42, A40 and S-100B protein, using a set of commercially available assays.Tau protein levels were lower in DLB in first and second LP compared to AD and decreased during course of both groups. P-tau levels were increased in AD and DLB and decreased during follow-up. A42 and A40 remained relatively stable during follow-up but we found a slight increase of the median A42 level in DLB, whereas in AD, A42 tends to decrease during follow-up. S-100B protein increased during follow-up in both diseases.The protein dynamics in DLB and AD are relatively similar. S-100B protein may be a useful marker for follow-up in neurodegenerative diseases but has to be analysed in longer follow-up periods. Tau protein may be used to differentiate between DLB and AD.Follow-up CSF analyses are of limited value for the differentiation of AD and DLB. We conclude that more specific markers have to be established for the differentiation and follow-up of these diseases.     

Fluctuating cognition and different cognitive and behavioural profiles in Parkinson’s disease with dementia: comparison of dementia with Lewy bodies and Alzheimer’s disease

To examine the occurrence of fluctuating cognition (FC) in a group of patients with Parkinson’s disease with dementia (PDD), and to determine whether the presence of FC in PDD is associated with a pattern of cognitive and behavioural disturbances similar to the one shown by patients affected by dementia with Lewy bodies (DLB), a cluster analysis was carried out on the scores obtained by 27 PDD patients on the Clinician Assessment of Fluctuation Scale (CAF). The analysis separated the PDD patients into two subgroups, called PDD non-fluctuators (PDDNF; CAF ≤ 2) and PDD fluctuators (PDDF; CAF > 2). The two groups underwent a cognitive and behavioural evaluation. Their scores were compared with those obtained by DLB and Alzheimer’s disease (AD) patients. When exploring the cognitive performance of the patients with the Dementia Rating Scale-2 (DRS-2), PDDF had a similar pattern of impairments compared to DLB, which involved prevalently the attention and initiation/perseveration domains, and which was significantly more pronounced compared to that shown by PDDNF. The main behavioural finding of the study was the similar incidence of visual hallucinations in the PDDF and DLB groups, which was significantly higher compared to PDDNF and AD. Our results confirmed the hypothesis that subgroups with different cognitive profiles exist within PDD and that the occurrence of FC is the clinical variable associated with a DLB pattern of impairment in PDD. In conclusion, our study suggests that when FC occurs in PDD this syndrome becomes clinically undistinguishable from DLB.     

Pathological entity of dementia with Lewy bodies and its differentiation from Alzheimer’s disease

We reclassified the pathological subtypes of dementia with Lewy bodies (DLB), based on both Lewy pathology and Alzheimer pathology, to clarify the pathological entity of DLB and the boundary between DLB and Alzheimers disease (AD) in autopsied cases, using both pathological and immunohistochemical methods. DLB was classified as either limbic type or neocortical type according to the degree of Lewy pathology including Lewy bodies (LB) and LB-related neurites by our staging, and was classified as pure form, common form or AD form according to the degree of Alzheimer pathology including neurofibrillary tangles (NFT) and amyloid deposits by Braak staging. These combined subtypes were lined up on a spectrum, not only with Lewy pathology but also with other DLB-related pathologies including Alzheimer pathology, neuronal loss in the substantia nigra, spongiform change in the transentorhinal cortex and LB-related neurites in the CA2–3 region. In contrast, the Lewy pathology of AD did not meet the stages of Lewy pathology in DLB, and there were scarcely any similarities in other DLB-related pathologies between AD and DLB. In addition, the Lewy pathology of AD had characteristics different from that of DLB, including the coexistence rate of LB with NFT, and the immunohistochemical and immunoelectron microscopic findings of LB and LB-related neurites. These findings suggest that DLB is a distinctive pathological entity that can be differentiated from AD, although it shows some pathological subtypes.     

Alzheimer’s disease pathology in motor cortex in dementia with Lewy bodies clinically mimicking corticobasal degeneration

We report here a 70-year-old woman whose initial clinical presentation suggested corticobasal degeneration, but autopsy revealed dementia with Lewy bodies (DLB) with severe Alzheimer’s disease (AD)-type pathology accentuated in the motor cortex, in conjunction with a high burden of both cortical and brain stem LB. Review of the literature disclosed four patients with AD whose peri-Rolandic region was particularly involved by the disease and who exhibited similar clinical and neuropathological findings as in our patient except they lacked LB. It appears that DLB if associated with severe AD-type pathology can, like some unusual cases of AD, mimic corticobasal degeneration. Received: 20 October 1998 / Revised, accepted: 15 February 1999     

Staging TDP-43 pathology in Alzheimer’s disease

TDP-43 immunoreactivity occurs in 19–57 % of Alzheimer’s disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (limbic) or hippocampus and neocortex (diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17 %); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25 %); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31 %); stage IV showed further spread into inferior temporal cortex (20 %); and stage V showed involvement of frontal cortex and basal ganglia (7 %). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.     

Frontotemporal dementia in a large Swedish family is caused by a progranulin null mutation

Mutations in the progranulin (PGRN) gene have recently been identified in families with frontotemporal lobar degeneration and ubiquitin-positive brain inclusions linked to chromosome 17q21. We have previously described a Swedish family displaying frontotemporal dementia with rapid progression and linkage to chromosome 17q21. In this study, we performed an extended clinical and neuropathological investigation of affected members of the family and a genetic analysis of the PGRN gene. There was a large variation of the initial presenting symptoms in this family, but common clinical features were non-fluent aphasia and loss of spontaneous speech as well as personality and behavioural changes. Mean age at onset was 54 years with disease duration of close to 4 years. Neuropathological examination revealed frontotemporal neurodegeneration with ubiquitin and TAR DNA binding protein-43 immunoreactive intraneuronal inclusions. Mutation screening of the PGRN gene identified a 1 bp deletion in exon 1 causing a frameshift of the coding sequence and introducing a premature termination codon in exon 2 (Gly35GlufsX19). Analysis of PGRN messenger RNA (mRNA) levels revealed a considerable decrease in lymphoblasts from mutation carriers and fragment size separation, and sequence analysis confirmed that the mutated mRNA allele was almost absent in these samples. In conclusion, the PGRN Gly35fs mutation causes frontotemporal dementia with variable clinical presentation in a large Swedish family, most likely through nonsense-mediated decay of mutant PGRN mRNA and resulting haploinsufficiency.     

The molecular genetics and neuropathology of frontotemporal lobar degeneration: recent developments

The past year has seen a number of significant advances in our understanding of the neuropathological and molecular genetic basis of frontotemporal lobar degeneration (FTLD). Whereas, in the past, most attention focused on FTLD associated with tau-based pathology and microtubule associated protein tau gene (MAPT) mutations, there has recently been greater attention paid to non-tau FTLD. FTLD with tau-negative, ubiquitinated inclusions (FTLD-U) is now recognized as the most common pathology associated with clinical FTLD. Mutations in the progranulin gene (PGRN) have been identified as the cause of FTLD-U linked to chromosome 17. A rapidly growing number of PGRN mutations have been identified, and to date, all appear to cause FTLD by reducing the amount of functional PGRN protein (haploinsufficiency). The neuropathology associated with each of the known non-MAPT FTLD genes and loci (PGRN, valosin-containing protein gene, CHMP2B and 9p), has been shown to be a specific subtype of FTLD-U. The ubiquitinated pathological protein in FTLD-U has been identified as TAR deoxyribonucleic acid-binding protein with M _r 43 kDa (TDP-43). Immunohistochemical and biochemical studies of TDP-43 have helped to clarify the relationship between different sub-types of FTLD-U and related conditions. It is anticipated that these discoveries will facilitate the development of new diagnostic tests and therapeutics.     

Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy

TAR DNA-binding protein of 43 kDa (TDP-43) is a major component of the pathological inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy, also called FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and motor neuron disease (MND). TDP-43 is predominantly expressed in the nucleus and regulates gene expression and splicing. In FTLD with TDP-43 proteinopathy, neuronal inclusions present variably as cytoplasmic inclusions (NCIs), dystrophic neurites (DNs), and intranuclear inclusions (NIIs), leading to a fourfold neuropathological classification correlating with genotype. There have been few fine structural studies of these inclusions. Thus, we undertook an immunoelectron microscopic study of FTLD with TDP-43 proteinopathy, including sporadic and familial cases with progranulin (GRN) mutation. TDP-43-immunoreactive inclusions comprised two components: granular and filamentous. Filament widths, expressed as mean (range) were: NCI, 9 nm (4–16 nm); DN, 10 nm (5–16 nm); NII, 18 nm (9–50 nm). Morphologically distinct inclusion components may reflect the process of TDP-43 aggregation and interaction with other proteins: determining these latter may contribute towards understanding the heterogeneous pathogenesis of FTLD with TDP-43 proteinopathy. Supported by grants to JRT and NJC from the Wellcome Trust (GR066166AIA), and National Institute on Aging of the National Institutes of Health (P50 AG05681 and P01 AG03991) to NJC.     

The complex aetiology of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is now a widely recognised form of dementia. This heterogeneous disease has been of particular interest to geneticists due to its high rate of heritability with up to 40% of patients reporting a family history of the disease in at least one extra family member. There have been several chromosome loci linked to this disorder and three genes have already been identified. Remarkably, it has been recently demonstrated that 2 of these are only 1.7 Mb from one another on chromosome 17q21, these being tau and progranulin. The identification of these genes has contributed greatly to our understanding of the differing neuropathologies associated with FTLD. Furthermore, the discovery that TDP-43 is a component of the neuronal inclusions seen in the most common neuropathological subtype has also helped expand the biochemical pathways that are the focus of much FTLD research. Nevertheless, other genes causing FTLD remain to be identified and their biology elucidated before we have a complete understanding of the complex aetiology of this disease.     

Progranulin and frontotemporal lobar degeneration

Frontotemporal lobar degeneration is the term used to describe the non-Alzheimer clinical syndromes of frontotemporal dementia, semantic dementia and progressive non-fluent aphasia, regardless of the underlying neuropathological features. Considerable progress has been made in recent years in our understanding of the aetiology of this disorder, notably the identification of mutations in tau and progranulin genes, both on chromosome 17q21. Mutations in tau appear to affect the ability of tau to bind microtubules and/or increase this protein’s ability to form fibrils. In contrast, progranulin mutations cause haploinsufficiency leading to TDP-43 accumulation. These genes collectively account for 10–20% of FTLD. However, it is clear that much remains to be discovered before our knowledge of this heterogeneous condition is complete.     

The neuropathology and clinical phenotype of FTD with <Emphasis Type="Italic">progranulin</Emphasis> mutations

Mutations in the progranulin gene (PGRN), on chromosome 17q21, have recently been identified as a major cause of familial frontotemporal dementia (FTD). These cases have a characteristic pattern of neuropathology that is a distinct subtype of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), with lentiform neuronal intranuclear inclusions being a consistent feature. There is no abnormal accumulation of PGRN protein in the brain and immunohistochemical and biochemical analysis indicates that the ubiquitinated pathological protein is TDP-43. In these families, FTD is inherited in an autosomal dominant fashion with high penetrance. The clinical phenotype is usually a combination of behavioural abnormality and language disturbance that is most often a form of primary progressive aphasia. Mild parkinsonism is common but motor neuron disease is notably rare. Marked variation in the disease course and clinical features are common, not only between families with different mutations, but also within individual families. This degree of clinical variability makes it difficult to predict which cases of familial FTD will turn out to have a PGRN mutation.     

TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD

Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is the most common neuropathological subtype of frontotemporal dementias. While TDP-43 is the pathologic protein in the majority of FTLD-U cases, small numbers of cases have recently been reported with TDP-43-negative FTLD-U pathology. To determine the frequency and to define the clinico-pathological spectrum of TDP-43-negative FTLD-U, we re-evaluated 44 cases with a previous diagnosis of FTLD-U or dementia lacking distinctive histopathology. We identified nine cases (20%) with TDP-43-negative FTLD-U pathology by immunohistochemistry and confirmed the absence of pathological TDP-43 by biochemical analysis. All patients presented with sporadic early-onset frontotemporal dementia with predominant behavioral and personality changes. Besides ubiquitin-positive neuronal cytoplasmic inclusions, the most intriguing neuropathological feature was the presence of ubiquitin-positive neuronal intranuclear inclusions (NIIs), often with curved or twisted morphology, in the neocortex, hippocampus, brainstem, and spinal cord. Double-label immunofluorescence revealed an unusual and distinct immunoreactivity profile for these NIIs, with ubiquitin-immunoreactivity, but absence of p62 labeling. The highly consistent clinical and neuropathological phenotype supports the concept that TDP-43-negative FTLD-U should be considered as a new clinicopathological FTLD entity.