Estrella Gómez-Tortosa

Clinical and quantitative pathologic correlates of dementia with Lewy bodies.

Objectives: To examine the distribution of cortical Lewy bodies (LB) and their contribution to the clinical syndrome in dementia with LB (DLB) and to address their relationship to the pathologic markers of AD and PD. Methods:We studied 25 cases meeting neuropathologic criteria for DLB: 13 cases without AD (Braak stage I or II) and 12 cases with concomitant AD changes (Braak stages III to V). Age at onset, disease duration, and clinical symptoms were reviewed for each case. We quantified the regional distribution of LB in substantia nigra, paralimbic areas (cingulate gyrus, insula, entorhinal cortex, and hippocampus), and neocortex (frontal and occipital association areas) using anti–α-synuclein immunostaining. We compared the LB pathology between groups of patients with different symptoms at onset or with specific clinical phenotypes. Results: There were no significant differences in clinical symptoms or LB density between cases with or without concomitant AD. LB density showed a consistent gradient as follows: substantia nigra > entorhinal cortex > cingulate gyrus > insula > frontal cortex > hippocampus > occipital cortex. LB density in substantia nigra and neocortex was not significantly different in cases that started with parkinsonism compared with those that started with dementia. There were no significant differences in LB density in any region among patients with or without cognitive fluctuations, visual hallucinations, delusions, recurrent falls, or parkinsonism. Duration of the disease correlated with a global LB burden for each case (p = 0.02) but did not correlate with LB density in any individual area. Paralimbic and neocortical LB density were highly correlated with each other (p < 0.0001), but neither of these correlated well with the number of LB in substantia nigra. LB density did not correlate with Braak stage or frequency of neuritic plaques. Conclusions: There is a consistent pattern of vulnerability to LB formation across subcortical, paralimbic, and neocortical structures that is similar for DLB cases with or without concomitant AD. Paralimbic and neocortical LB do not correlate with LB in substantia nigra, suggesting that DLB should not be considered just a severe form of PD. LB density correlates weakly with clinical symptoms and disease duration.

α-Synuclein immunoreactivity in dementia with Lewy bodies: morphological staging and comparison with ubiquitin immunostaining

Abstractα-Synuclein is a presynaptic protein recently identified as a specific component of Lewy bodies (LB) and Lewy neurites. The aim of this study was to assess the morphology and distribution of α-synuclein immunoreactivity in cases of dementia with LB (DLB), and to compare α-synuclein with ubiquitin immunostaining. We examined substantia nigra, paralimbic regions (entorhinal cortex, cingulate gyrus, insula and hippocampus), and neocortex (frontal and occipital association cortices) with double α-synuclein and ubiquitin immunostaining in 25 cases meeting neuropathological criteria for DLB. α-Synuclein immunostaining was more specific than ubiquitin immunostaining in that it differentiated LB from globose tangles. It was also slightly more sensitive, staining 4–5% more intracytoplasmic structures, especially diffuse α-synuclein deposits that were ubiquitin negative. In addition to LB, α-synuclein staining showed filiform and globose neurites in the substantia nigra, CA2–3 regions of the hippocampus, and entorhinal cortex. A spectrum of α-synuclein staining was seen in substantia nigra: from diffuse “cloud-like” inclusions to aggregated intracytoplasmic inclusions with variable ubiquitin staining to classic LB. We hypothesize that these represent different stages in LB formation.

Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies

Objective: To address the relationship between dementia and neuropathologic findings in dementia with Lewy bodies (DLB) in comparison with AD. Methods: We evaluated the clinical presentation of autopsy-confirmed DLB in comparison with AD according to new Consortium on DLB criteria and compared the two conditions using quantitative neuropathologic techniques. This clinicopathologic series included 81 individuals with AD, 20 with DLB (7 “pure” DLB and 13 “DLB/AD”), and 33 controls. We counted number of LB, neurons, senile plaques (SP), and neurofibrillary tangles (NFT) in a high order association cortex, the superior temporal sulcus (STS), using stereologic counting techniques. Results: The sensitivity and specificity of Consortium on DLB clinical criteria in this series for dementia, hallucinations, and parkinsonism are 53% and 83%, respectively, at the patient’s initial visit and 90% and 68%, respectively, if data from all clinic visits are considered. In pathologically confirmed DLB brains, LB formation in an association cortical area does not significantly correlate with duration of illness, neuronal loss, or concomitant AD-type pathology. Unlike AD, there is no significant neuronal loss in the STS of DLB brains unless there is concomitant AD pathology (neuritic SP and NFT). Conclusions: The evaluation of new Consortium on DLB criteria in this series highlights their utility and applicability in clinicopathologic studies but suggests that sensitivity and specificity, especially at the time of the first clinical evaluation, are modest. The lack of a relationship of LB formation to the amount of Alzheimer-type changes in this series suggests that DLB is a distinct pathology rather than a variant of AD.

C9ORF72 hexanucleotide expansions of 20–22 repeats are associated with frontotemporal deterioration

Objective: Expansions of more than 30 hexanucleotide repetitions in the C9ORF72 gene are a common cause of frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). However, the range of 20–30 repetitions is rarely found and still has unclear significance. A screening of our cohort of cases with FTD (n = 109) revealed 4 mutation carriers (>30 repetitions) but also 5 probands with 20–22 confirmed repetitions. This study explored the possible pathogenic correlation of the 20–22 repeats expansion (short expansion). Methods: Comparison of clinical phenotypes between cases with long vs short expansions; search for segregation in the families of probands with short expansion; analysis of the presence of the common founder haplotype, described for expansions >30 repeats, in the cases having the short expansion; and analysis of the distribution of hexanucleotide repeat alleles in a control population. Results: No different patterns were found in the clinical phenotype or aggressiveness of the disease when comparing cases with long or short expansions. Cases in both groups had psychiatric symptoms during 1–3 decades before evolving insidiously to cognitive deterioration. The study of the families with short expansion showed clear segregation of the 20–22 repeats allele with the disease. Moreover, this 20–22 repeats allele was associated in all cases with the pathogenic founder haplotype. None of 216 controls had alleles with more than 14 repetitions. Conclusions: Description of these families suggests that short C9ORF72 hexanucleotide expansions are also related to frontotemporal cognitive deterioration.

Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia

Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P< 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearmans ρ = 0.743, P = 1.05 × 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.

Senile dementia associated with amyloid β protein angiopathy and tau perivascular pathology but not neuritic plaques in patients homozygous for the APOE-ε4 allele

Abstract Amyloid β protein deposition in cortical and leptomeningeal vessels, causing the most common type of cerebral amyloid angiopathy, is found in sporadic and familial Alzheimer’s disease (AD) and is the principal feature in the hereditary cerebral hemorrhage with amyloidosis, Dutch type. The presence of the Apolipoprotein E (APOE)-ɛ4 allele has been implicated as a risk factor for AD and the development of cerebral amyloid angiopathy in AD. We report clinical, pathological and biochemical studies on two APOE-ɛ4 homozygous subjects, who had senile dementia and whose main neuropathological feature was a severe and diffuse amyloid angiopathy associated with perivascular tau neurofibrillary pathology. Amyloid β protein and ApoE immunoreactivity were observed in leptomeningeal vessels as well as in medium-sized and small vessels and capillaries in the parenchyma of the neocortex, hippocampus, thalamus, cerebellum, midbrain, pons, and medulla. The predominant peptide form of amyloid β protein was that terminating at residue Val40, as determined by immunohistochemistry, amino acid sequence and mass spectrometry analysis. A crown of tau-immunopositive cell processes was consistently present around blood vessels. DNA sequence analysis of the Amyloid Precursor Protein gene and Presenilin-1 (PS-1) gene revealed no mutations. In these APOE-ɛ4 homozygous patients, the pathological process differed from that typically seen in AD in that they showed a heavy burden of perivascular tau-immunopositive cell processes associated with severe amyloid β protein angiopathy, neurofibrillary tangles, some cortical Lewy bodies and an absence of neuritic plaques. These cases emphasize the concept that tau deposits may be pathogenetically related to amyloid β protein deposition.

Clinical and Neuropathological Correlates of Dementia with Lewy Bodies

Abstract: Dementia with Lewy bodies (DLB) is characterized pathologically by widespread Lewy body (LB) neuronal inclusions in the brain, but the contribution of LBs to the clinical syndrome of dementia and parkinsonism is unclear. In a clinical‐pathological study of 25 cases with DLB, we examined the regional neuroanatomical distribution of Lewy‐related pathology using α‐synuclein immunostaining to evaluate the relationship between LBs, neuronal loss, Alzheimer‐type changes, and the clinical phenotype. Compared to traditional ubiquitin immunostaining, α‐synuclein immunohistochemistry was more specific and slightly more sensitive, staining about 5% more intracytoplasmic structures. There was a consistent pattern of vulnerability to LB formation across subcortical, paralimbic, limbic, and neocortical structures, which was independent of concomitant Alzheimer‐type changes. There were no significant differences in regional LB densities among patients with or without cognitive fluctuations, visual hallucinations, delusions, recurrent falls or parkinsonism. Duration of disease correlated weakly with LB density. There was no neuronal loss in superior temporal sulcus or entorhinal cortex in pure DLB cases compared to nondemented controls. Thus, DLB is characterized by a specific neuroanatomical vulnerability to LB pathology, distinct from AD pathology, with a complicated relationship to clinical symptoms.

Dementia with Lewy Bodies

In the last decade, a new degenerative dementia, probably the second most common after Alzheimers disease (AD), has been increasingly recognized under the consensus name of dementia with Lewy bodies (DLB). This article reviews current clinical, genetic, and pathological DLB data and indicates directions for future research. DLB overlaps in clinical, pathological, and genetic features with AD and Parkinsons disease (PD). Clinically, it is characterized by progressive cognitive impairment with significant fluctuations in alertness, parkinsonism, and psychosis with recurrent hallucinations. The neuropathological hallmarks are the intracytoplasmic inclusions in substantia nigra typical of PD, known as Lewy bodies (LB) but distributed widely throughout paralimbic and neocortical regions. Most of the cases also coexist with a plaque predominant AD. It is probably the unique and differential distribution of the lesions throughout cortical and subcortical structures in each of these disorders that supports a specific clinical syndrome and may ultimately prove most useful in understanding their different etiologies. Several genes have recently been implicated in LB formation. Special interest arises from mutations in the alpha-synuclein gene, which appears to be responsible for autosomal dominant PD in several kindreds. This gene encodes a presynaptic protein, a fragment of which is present in AD plaques. Recent studies show intense and quite specific alpha-synuclein immunoreactivity in LB and related neurites, suggesting a potential role of this protein in the aggregation or precipitation of LB inclusions.

Clinical-Genetic Correlations in Familial Alzheimer's Disease Caused by Presenilin 1 Mutations

We describe the clinical phenotype of nine kindred with presenile Alzheimers disease (AD) caused by different presenilin 1 (PS1) point mutations, and compare them with reported families with mutations in the same codons. Mutations were in exon 4 (Phe105Val), exon 5 (Pro117Arg, Glu120Gly), exon 6 (His163Arg), exon 7 (Leu226Phe), exon 8 (Val261Leu, Val272Ala, Leu282Arg), and exon 12 (Ile439Ser). Three of these amino acid changes (Phe105Val, Glu120Gly, and Ile439Ser) had not been previously reported. Distinct clinical features, including age of onset, symptoms and signs associated with the cortical-type dementia and aggressiveness of the disease, characterized the different mutations and were quite homogeneous across family members. Age of onset fell within a consistent range: some mutations caused the disease in the thirties (P117R, L226F, V272A), other in the forties (E120G, H163R, V261L, L282R), and other in the fifties (F105V, I439S). Associated features also segregated with specific mutations: early epileptic activity (E120G), spastic paraparesis (V261L), subcortical dementia and parkinsonism (V272A), early language impairment, frontal signs, and myoclonus (L226F), and late myoclonus and seizures (H163R, L282R). Neurological deterioration was particularly aggressive in PS1 mutations with earlier age of onset such as P117R, L226F, and E120G. With few exceptions, a similar clinical phenotype was found in families reported to have either the same mutation or different amino acid changes in the same codons. This series points to a strong influence of the specific genetic defect in the development of the clinical phenotype.

TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

We investigated the mutation spectrum of the TANK‐Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early‐Onset Dementia Consortium. We assessed pathogenicity of predicted protein‐truncating mutations by measuring loss of RNA expression. Functional effect of in‐frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB‐induced luciferase reporter assay and measuring phosphorylated TBK1. The protein‐truncating mutations led to the loss of transcript through nonsense‐mediated mRNA decay. For the in‐frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high‐risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD‐ALS.