Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation.

OBJECTIVE: Large kindreds segregating familial Alzheimer disease (FAD) offer the opportunity of studying clinical variability as observed for presenilin 1 (PSEN1) mutations. Two early-onset FAD (EOFAD) Calabrian families with PSEN1 Met146Leu (ATG/CTG) mutation constitute a unique population descending from a remote common ancestor. Recently, several other EOFAD families with the same mutation have been described worldwide. METHODS: We searched for a common founder of the PSEN1 Met146Leu mutation in families with different geographic origins by genealogic and molecular analyses. We also investigated the phenotypic variability at onset in a group of 50 patients (mean age at onset 40.0 +/- 4.8 years) by clinical, neuropsychological, and molecular methodologies. RESULTS: EOFAD Met146Leu families from around the world resulted to be related and constitute a single kindred originating from Southern Italy before the 17th century. Phenotypic variability at onset is broad: 4 different clinical presentations may be recognized, 2 classic for AD (memory deficits and spatial and temporal disorientation), whereas the others are expressions of frontal impairment. The apathetic and dysexecutive subgroups could be related to orbital-medial prefrontal cortex and dorsolateral prefrontal cortex dysfunction. CONCLUSIONS: Genealogic and molecular findings provided evidence that the PSEN1 Met146Leu families from around the world analyzed in this study are related and represent a single kindred originating from Southern Italy. The marked phenotypic variability might reflect early involvement by the pathologic process of different cortical areas. Although the clinical phenotype is quite variable, the neuropathologic and biochemical characteristics of the lesions account for neurodegenerative processes unmistakably of Alzheimer nature.

[Familial fronto-temporal dementia with brain stem ubiquitin-positive neuronal inclusions]. / Démence fronto-temporale familiale avec inclusions marquées par l'anti-ubiquitine dans le tronc cérébral.

INTRODUCTION: Fronto-temporal dementias (FTD) were described a century ago on the macroscopic basis of frontal and/or temporal lobe atrophy. Progress in neuropathology, immunohistochemistry, biochemistry and genetics has since shown that they are heterogeneous entities, encompassing many different diseases with similar clinical presentations. A few, such as tauopathies due to mutations of the gene coding for tau protein (MAPtau form a well-defined group. Definition and grouping of other types of FTD is still problematic. MATERIAL AND METHOD: We studied a family where the mother and 4/8 children were affected with FTD. Clinical presentation was typical of FTD. Onset was ill-defined with early (at age 40 years or less) personality changes. The clinical course was protracted (about 30 years). For a long period, the patients were able to live in the community in spite of obvious signs such as hyperorality and loss of verbal initiative; operative orientation as to place was preserved for a long time: a mute patient was still able to drive. Signs of extrapyramidal or motoneuron involvement were not observed. RESULTS: The genetic study failed to detect any mutation in MAPtau; the lod score for flanking markers was positive but not significant. Biochemical study showed no qualitative abnormality in tau protein. Neuropathological study of one affected subject showed brain atrophy (962 g), with elective frontal lobe involvement. Cortical nerve cell loss was more marked in superficial layers and in frontal areas; glia was inconspicuous; pseudolaminar spongiosis was present in the more severely affected zones. No argentophilic "Pick bodies" were seen; ubiquitin-positive, tau-negative round inclusions were present in the cytoplasm of fascia dentata neurones. "Tangles" were mostly restricted to the entorhinal cortex, partly correlated with tau immunoreactivity, but better with ubiquitin immunoreactivity. Large, ovoid or reniform, moderately dense, spongy, granular or filamentous argentophilic cytoplasmic nerve cell inclusions were observed. They were ubiquitin-positive, but did not react with other antibodies, particularly anti-tau. They were present in swollen nerve cells in the deeper cortical layers but were most conspicuous in the brain stem: in the magnocellular reticular nuclei (e.g. nucleus centralis pontis), in the pes pontis, in the inferior olive and in motor nuclei, especially in the trigeminal motor nucleus. They were not associated with nerve cell loss, atrophy nor pycnosis. Cerebellar relay nuclei neurones were swollen, and their cytoplasm contained argentophilic filaments. CONCLUSION: In our opinion, "ubiquitinopathy" would be non-specific and "Motor Neuron Disease-Inclusion Dementia" (MNDID) would not be satisfactory as a diagnosis for the present cases of FTD. Hopefully, progress in genetics may allow a causal, and thence definitive, classification.

A Heidenhain variant of Creutzfeldt-Jakob disease: forensic implication.

To investigate whether typical clinical, diagnostic and neuropathological findings can be identified in a patient with a postmortem diagnosis of a Heidenhain variant of Creutzfeldt-Jakob disease (CJD). We report a new case of CJD in a rare variant. A man admitted to hospital with cefalea and vision disorder. Clinical and neurological examination showed headache, vision reduction, psychomotor anxiety and progressive torpor. The patient died 4 h after admission to hospital. The autopsy findings included marked encephalic vascular congestion. Hystoneurology examination showed no macroscopic anomaly. Microscopy findings included neuronal loss, gliosis in striate area with arachnoid cells and cerebellum microspongiosis. Creutzfeldt-Jakob disease is a rare neurodegenerative human disorder. The prion hypothesis as an explanatory model is currently favoured by majority of researchers. A disease course described by Heidenhain including the leading symptoms of a visual disorder and rapid progression. This report emphasize the multidisciplinary role (forensic, neurogenetic and neurohistologic) for diagnosis and to standardize a protocol to investigate.

A large Calabrian kindred segregating frontotemporal dementia.

Frontotemporal dementia (FTD) displays significant neuropathological and genetic heterogeneity among and within affected families. An early diagnosis is often difficult because cognitive symptoms are manifest only at a late stage of the disease. We have been studying a large pedigree segregating frontotemporal dementia (FTD) to which belong 34 identified affected persons, 11 of whom were personally examined. The kindred has been genealogically reconstructed; all FTD patients have been linked to the same ancestors who lived in the early 18(th) century (11 generations before the present one). Autosomal dominant transmission was evident. Clinical features were uniform within the kindred and met the Lund-Manchester criteria. Personality changes with absence of insight, lack of empathy and of social awareness manifested up to 5 years before medical advice was sought. Loss of fluency was the earliest neuropsychological sign, in the absence of memory, orientation and praxis deficits, which evolved late, together with hyperorality. Akinesia was observed early, rigidity appeared late, tremor was absent. Two patients showed myoclonus late in their evolution. No ALS signs were observed in this kindred. Mutations of the MAPt gene, coding for the Tau protein, were not detected in affected family members. Linkage studies excluded chromosomes 3 and 9 and gave indeterminate results that were model dependent for chromosome 17.

Comparison of clinical and pathological phenotypes in two ethnically and geographically unrelated pedigrees segregating an equivalent presenilin 1 mutation.

At least 30 different missense mutations have been identified within the presenilin 1 (PS1) gene in pedigrees transmitting familial Alzheimer's disease. The authors investigated the clinical and pathological features of affected members of two pedigrees segregating a PS1 Met146Leu mutation. Genetic relationships between these pedigrees can be effectively excluded on the basis of genealogical data and the fact that although the amino acid substitution is identical, the nucleotide mutations are different. The clinical picture shows remarkable similarities in the neurological and the neuropathological findings between the two pedigrees. This general clinical and pathological concordance argues that much of the disease phenotype arises directly from the effects of the amino acid substitution within the PS1 protein itself. Clinical differences could arise from a direct effect of the difference in base sequence or, alternatively, from the effect of genetic or environmental modifiers.

Prominent psychiatric features and early onset in an inherited prion disease with a new insertional mutation in the prion protein gene.

In five generations of the French M-E kindred, 11 members are now known to be or have been affected by a form of spongiform encephalopathy previously recorded as Gerstmann-Sträussler-Scheinker disease. Mean age at onset was 28 years (range 21-34 years). In six instances, these patients were hospitalized in psychiatric institutions with various diagnoses, the most frequent being mania or mania-like symptoms. Dementia occurred progressively after a lengthy course. Histological studies showed atrophy of the cerebellar molecular layer, which contained kuru and multicentric plaques labelled with anti-prion protein antibodies. Spongiosis was not prominent and remained largely limited to the periphery of plaques; it was more marked in the thalamus, where plaques were scarce. A 192 base pair (bp) insert (eight extra repeats of 24 bp) in the octapeptide coding region of the prion protein gene (PRNP) within a codon-129 methionine allele was found in four symptomatic subjects. Early age at onset, the prominence of psychiatric symptoms and the long course of the disease are noticeable clinical features in this family with an inherited prion disease due to a new insertional mutation in PRNP.

Modifications of oligodendroglial cells in spongiform encephalopathies.

Although gray matter lesions involving neurones and astrocytes are prominent in human transmissible spongiform encephalopathies (TSE), white matter lesions have also been occasionally observed. Secondary (Wallerian) degeneration and direct myelin damage have been invoked, but the physiopathology of white matter involvement is still debated. We performed an immunohistochemistry study with anti-PrP antibodies of autopsy material of four patients with Creutzfeldt-Jakob disease (CJD), together with transmission electron microscopy (TEM) studies of conventionally processed biopsy specimens of the same patients. Light microscopy immunolabeling was observed as arrays adjacent to myelinic fibers and as a clumps adjacent to oligodendroglial nuclei; both cerebrum and cerebellum were involved. At the ultrastructural level, two types of intracellular inclusions were seen in the white matter. They were associated with dense lysosomes in oligodendroglial perikarya and in their processes. The inclusions were made of finely fibrillar, paracrystalline, amorphous, or densely osmophilic material. Thus, our findings may suggest that white matter involvement in spongiform encephalopathy is due to direct modifications of oligodendroglial cell associated with abnormal metabolism of PrP.

Putative neurosurgical transmission of Creutzfeldt-Jakob disease with analysis of donor and recipient: agent strains.

A woman, aged 59 years, underwent a cortical biopsy that led to the diagnosis of Creutzfeldt-Jakob disease (CJD). A man, aged 46 years, underwent cranial surgery in the same department 3 days later for brain contusion, with an uneventful recovery. Twenty six months later, he developed clinical signs of CJD with a typical EEG pattern. Both cases exhibited features of the 'ataxic' form of the disease with depletion of cerebellar granule cells, without kuru plaques or PrP deposits. PrP deposits were immuno-histochemically observed in the cerebrum, spinal cord and peripheral nerve. Molecular genetic analysis performed on brain tissue revealed the codon 129 polymorphism to be Met129Met in the donor and Met129Val in the recipient. The shared 'cerebellar' phenotype and the genotypic discrepancy between the two patients lead us to postulate that the 'cerebellar' agent strain plays a major role in CJD phenotype and transmission.

Widespread immunoreactivity of presenilin in neurons of normal and Alzheimer's disease brains: double-labeling immunohistochemical study.

The immunolocalization of presenilin in human brain was studied using two antibodies raised against different portions of presenilin 1 (S182) protein. A granular staining was found in the cytoplasm of neurons in cortical layers III and V. One of the antibodies, also reactive to presenilin 2 (E5-1) protein, additionally stained dendrites and axons. This was seen in normal brains as well as in brains affected by Alzheimer's disease. Less prominent immunolabeling was noted in some senile plaques. No relationship to neurofibrillary tangles was found in double-labeling experiments combined with anti-paired helical filament-tau antibody (AT8). The widespread expression of presenilin in normal brain suggests a physiological role of the protein.

Beta AP deposition and head trauma.

Head trauma is considered to be a risk factor for Alzheimer's disease, because a high prevalence of beta AP deposits has repeatedly been reported in patients who died within a few days following head injury. To evaluate this statement, we undertook two studies using immunohistochemistry for beta AP and found a surprisingly low prevalence of beta AP diffuse deposits. We first selected 23 patients aged 17-63 years, who died 0-76 days after head trauma. Using beta AP antibody at the usual dilution (1:100), we did not find any deposits. With a high concentration of antibody (dilution 1:2) we found beta AP diffuse deposits in one 46-year-old case. In a second study, 17 patients aged 60-79 years old, who died 1-35 days after head injury, were compared to a control group. We did not find any significant difference in the density of beta AP diffuse deposits between cases and controls using usual dilutions of beta AP antibody. The density of beta AP diffuse deposits was linked only to aging and the presence of senile plaques.

Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.

Some cases of Alzheimer's disease are inherited as an autosomal dominant trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcripts encoded within this region. One of these transcripts (S182) corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease. Because these changes occurred in conserved domains of this gene, and are not present in normal controls, they are likely to be causative of AD3.