Tau and Amyloid-ß Pathology in Japanese Forensic Autopsy Series Under 40 Years of Age: Prevalence and Association with APOE Genotype and Suicide Risk.

BACKGROUND: Aggregation of abnormal phosphorylated tau in brain stem areas may be a possible early pathological manifestation of Alzheimer's disease (AD). OBJECTIVE: This study aimed to explore the prevalence of cases with AD-related pathology in subjects <40 years of age and to explore the association of such pathology, neuropsychiatric symptoms, and APOE genotype. METHOD: We conducted brain immunohistochemistry for 189 cases <40 years of age (mean±standard deviation age 25.3±13.1 years). Tau positive cases were then assessed for the distribution of tau pathology in the locus ceruleus (LC), raphe nucleus (RN), and entorhinal cortex (ErC), and the distinction between neuronal threads and cellular inclusions. Apolipoprotein E (APOE) genotype was also examined. RESULTS: Tau pathology was detected in 135 cases (71.4%; 13-39 years; only LC, 23 cases; only RN, 4 cases; only ErC, 35 cases; LC+RN, 3 cases; LC+ErC, 57 cases; all three regions, 10 cases). The prevalence of thread pathology was higher than that of cellular inclusions. Significantly higher prevalence of the APOEɛ2 allele were found in 10-39 years of age natural death cases (p < 0.05). Amyloid-ß deposition was found in only 7 cases, along with a significantly high frequency of the ɛ4 allele (p < 0.05). While a past history of psychiatric disease was a significant risk factor for suicide, AD-related pathology was not associated with suicide. CONCLUSIONS: Both the brain stem and entorhinal cortex was the initial site of tau pathology in many younger subjects. AD-related pathology may not be a significant accelerating factor for suicide in younger subjects.

Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy.

OBJECTIVE: Small-fiber sensory and autonomic symptoms are early presentations of familial amyloid polyneuropathy (FAP) with transthyretin (TTR) mutations. This study aimed to explore the potential of skin nerve pathologies as early and disease-progression biomarkers and their relationship with skin amyloid deposits. METHODS: Skin biopsies were performed in patients and carriers to measure intraepidermal nerve fiber (IENF) density, sweat gland innervation index of structural protein gene product 9.5 (SGII[PGP9.5]) and peptidergic vasoactive intestinal peptide (SGII[VIP]), and cutaneous amyloid index. These skin pathologies were analyzed with clinical disability assessed by FAP stage score (stage 0-4) and compared to neurophysiological and psychophysical tests. RESULTS: There were 70 TTR-mutant subjects (22 carriers and 48 patients), and 66 cases were TTR-A97S. Skin nerve pathologies were distinct according to stage. In carriers, both skin denervation and peptidergic sudomotor denervation were evident: (1) IENF density was gradually reduced from stage 0 through 4, and (2) SGII(VIP) was markedly reduced from stage 1 to 2. In contrast, SGII(PGP9.5) was similar between carriers and controls, but it declined in patients from stage 2. Skin amyloids were absent in carriers and became detectable from stage 1. Cutaneous amyloid index was correlated with SGII(PGP9.5) and stage in a multivariate mixed-effect model. When all tests were compared, only IENF density, SGII(PGP9.5), and cutaneous amyloid index were correlated with stage, and IENF density had the highest abnormal rate in carriers. INTERPRETATION: Biomarkers of sensory and sudomotor innervation exhibited a stage-dependent progression pattern, with sensory nerve degeneration as the early skin nerve pathology. Ann Neurol 2019;85:560-573.

Amyloid neuropathy with transthyretin mutations: overview and unique Ala97Ser in Taiwan.

Familial amyloid polyneuropathy (FAP) is a major etiology in differential diagnosis of symmetric axonalform polyneuropathy, but had been considered an unusual disease in Taiwan. We have reviewed the pathology of nerve biopsies and sequenced the entire 4 exons of transthyretin (TTR), the most common genetic mutation of FAP. Our studies indicated that the mutation of TTR at Ala97Ser (TTR Ala97Ser) was a new mutation only reported in ethnic Taiwanese, and this mutation accounted for the most frequent etiology of adult-onset pan-modality (involving motor, sensory, and autonomic components of peripheral nerves) polyneuropathy with the pathology of axonal degeneration type. Over the past 10 years, there have been advancements in the management of FAP due to TTR mutations: (1) symptomatic treatments of dyaautonomia, especially orthostatic hypotension, and (2) therapies with liver transplantation and small molecules to reduce or stabilize TTR.

Autonomic peripheral neuropathy.

Most generalized peripheral polyneuropathies are accompanied by clinical or subclinical autonomic dysfunction. There is a group of peripheral neuropathies in which the small or unmyelinated fibers are selectively targeted. In these neuropathies, autonomic dysfunction is the most prominent manifestation. The features associated with an autonomic neuropathy include impairment of cardiovascular, gastrointestinal, urogenital, thermoregulatory, sudomotor, and pupillomotor autonomic function.

[Multisystemic amyloidosis. Clinical study of 39 patients in Lebanon]. / Amyloses multisystémiques. Etude clinique de 39 patients au Liban.

OBJECTIVE: Clinical analysis of multisystem amyloidosis in Lebanon, by histological type. METHOD: Retrospective study of 39 cases of multisystem amyloidosis diagnosed histologically in a university hospital center between 1991 and 2002. It analyzed the following clinical data: age, gender, type of presentation, time from symptom onset to diagnosis, clinical features, concomitant diseases, family history of amyloidosis, biopsy sites, presence of urinary or serum monoclonal gammopathy, immunohistochemical type, prognosis and treatment. RESULTS: Median age at diagnosis was 56+/-18 years. The overall ratio of men to woman was 1.4. AL amyloidosis (amyloid light chain) accounted for 54% (21/39) of the cases, AA (amyloid-associated) amyloidosis 36% (14/39), while 10% (4/39) were not typed. Among the 21 cases of AL amyloidosis, 12 were idiopathic (57%) and 9 (43%) were associated with multiple myeloma; among the 14 cases of AA amyloidosis, 7 were associated with familial Mediterranean fever and 5 with chronic disorders. Proteinuria was often the first symptom. The initial manifestations in AL amyloidosis patients with myeloma were more often related to amyloidosis than to myeloma. Renal involvement was seen in 95% (37/39) of all cases (95% of AL versus 93% of AA), proteinuria in 87% of cases and renal failure in 72%. Cardiac amyloidosis (57% of AL versus 7% of AA; p>0.05), infiltration of the tongue (19% of AL versus 0% of AA; p>0.05) and neurological manifestations (24% of AL versus 7% of AA; p>0.05) were more frequent in AL amyloidosis. The 7 patients who died (18%) had AL amyloidosis (5 of them had myeloma). Heart failure was the most frequent cause of death related to amyloid. CONCLUSION: Multisystem amyloidosis is frequent in Lebanon and familial Mediterranean fever is still frequently associated with the secondary type. Accurate diagnosis and classification are essential for the prognosis and treatment of the disease. Poor prognosis was associated with the AL type, especially when accompanied by myeloma, and with cardiac amyloidosis.

[Recent advances of the treatment in metabolic disorders].

Familial amyloid polyneuropathy (FAP) and adult type (type II) citrullinemia are caused by metabolic disorders in liver: the vast majority of serum amyloid precursors (variant forms of transthyretin) in FAP are produced in liver and adult citrullinemia is ascribed to a deficiency of argininosuccinate synthetase (ASS), one of the five urea cycle enzymes in liver. Liver transplantation is, therefore, expected to correct the underlying metabolic abnormalities in both diseases. We performed partial liver transplantation using grafts from living donors for 13 patients with FAP and outcomes of 10 patients are satisfactory: polyneuritic and autonomic symptoms are gradually improving. The remaining 3 patients, all of whom were at advanced stages of the disease, had adverse postoperative results, presumably because of serious dysfunctions of amyloid-laden systemic organs. Similarly seven patients with adult citrullinemia received this transplantation and all recovered uneventfully. After operation plasma levels of ammonia and citrulline were soon normalized and five patients had returned to their previous social lives. Liver transplantation is a very promising therapy for the liver-based metabolic disorders.

Familial amyloidotic polyneuropathy type 1 in Brazil is associated with the transthyretin Val30Met variant.

UNLABELLED: Familial amyloidotic polyneuropathy type 1 (FAP1) is an inherited systemic amyloidosis that is secondary to the deposition of transthyretin (TTR) variants in peripheral nerves and in certain visceral organs. More than 50 distinct mutations have already been described in the TTR gene. Yet, the most common mutation found worldwide is a substitution of valine for methionine in position 30 (Val30Met). Currently, the variants of TTR in Brazilian FAP1 patients remain largely unknown and the aim of this study was to analyze the frequency of the TTR Val30Met mutation in such Brazilian subjects. METHODS: Thirty-two FAP1 patients belonging to 24 different families were studied for the presence of Val30Met variant by PCR-RFLP. RESULTS: All Brazilian FAP1 subjects studied were positive for the TTR Val30Met variant. As expected, all of them were heterozygous for the mutation. CONCLUSION: TTR Val30Met mutation was the sole TTR variant found in Brazilian FAP1 patients in this cohort, and it was present even in those subjects without a clear history of Portuguese ancestry.

Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan. Clinicopathological and genetic features.

Clinicopathological and genetic features were assessed on 35 Japanese families affected by late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy, FAP TTR Met30) whose siblings were unrelated to endemic Japanese foci. In these patients (50 years or older), the most common initial symptom was paraesthesias in the legs. Autonomic symptoms were generally mild and did not seriously affect daily activities. The male-to-female ratio was extremely high (10.7 : 1). A family history was evident in only 11 out of 35 families, and other patients were apparently sporadic. The rate of penetrance was very low. Symptomatic siblings of familial cases showed a late age of onset, male preponderance and clinical features similar to those of the probands. Asymptomatic carriers, predominantly female, were detected relatively late in life. The geographical distribution of these late-onset, FAP TTR Met30 cases was scattered throughout Japan. In three autopsy cases and 20 sural nerve biopsy specimens, neurons in sympathetic and sensory ganglia were relatively preserved. Amyloid deposition was seen in the peripheral nervous system, particularly in the sympathetic ganglia, dorsal root ganglia and proximal nerve trunks such as sciatic nerve. These abnormalities were milder than those seen in typical early-onset FAP TTR Met30, as observed in two Japanese endemic foci of this disease. While axonal degeneration was prominent in myelinated fibres, resulting in severe fibre loss, unmyelinated fibres were relatively preserved. Our cases of late-onset FAP TTR Met30 showed features distinct from those of typical early-onset FAP TTR Met30 that occurred in the two Japanese endemic foci. Factors responsible for clinicopathological differences between these two forms of FAP TTR Met30 need to be identified.

Two pairs of proven monozygotic twins discordant for familial amyloid neuropathy (FAP) TTR Met 30.

Twin studies are an important tool in medical genetics for the evaluation of the relative roles of genetic and non-genetic factors in several diseases. Familial amyloidotic polyneuropathy type I (FAP-I), TTR Met 30, was present in two sets of proven monozygotic (MZ) twins, one from Majorca and the other from Portugal. Monozygosity was established by analysis of DNA polymorphisms. Both pairs were discordant for age at onset and some clinical manifestations of FAP-I. We reviewed the differences in age at onset and clinical features in both sets and in two other pairs of presumed MZ twins with FAP-I and compared them with those in MZ twin pairs with other Mendelian disorders, such as neurofibromatosis type 1, Huntington's disease, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. We conclude that, in addition to the postulated modifying genes, there must be a significant contribution from non-genetic factors to the phenotypic variability of FAP-I (age at onset and clinical expression), either because of environmental differences or stochastic events during (or after) the twinning process.

Amyloid myopathy: clinicopathologic study of 16 cases.

Amyloid deposition in skeletal muscle is a well-recognized but rare occurrence. Sixteen such cases seen in a 17-year period (1979 to 1996) out of a total of 3,937 muscle biopsy specimens (0.004%) form this study group. Either Congo red or sulfated alcian blue stains were routinely performed in each biopsy to screen for amyloid. Patients in this study (eight men, eight women) ranged in age from 42 to 90 years (mean, 61 years) at initial presentation. The most common symptoms at presentation included weakness/fatigue (n = 10), autonomic symptoms (n = 8), and weight loss/decreased appetite (n = 7). Five patients had a concomitant malignancy (myeloma, n = 3; malignant carcinoid tumor, n = 1; melanoma, n = 1). Two patients had known hereditary forms of amyloidosis. Five patients had amyloid diagnosed on another organ biopsy (excluding peripheral nerve). Histologically, amyloid was deposited in the interstitium or perivascular region in 14 muscles and endomysial region in seven muscles. All cases were confirmed with Congo red staining (apple green birefringence) or by electron microscopic identification of fibrillary amyloid material. Scattered angular atrophic esterase-positive muscle myofibers indicative of acute denervation atrophy were seen in 14 muscles. Eight muscles showed small group atrophy, and seven showed myofiber type grouping. Scattered regenerating muscle fibers were seen in nine cases, degenerating myofibers in six, and foci of chronic endomysial and perivascular inflammation in two. Four muscles showed type II muscle fiber atrophy. A concomitant sural nerve biopsy specimen was evaluated in seven patients; all seven contained amyloid, confirmed either by Congo red staining or electron microscopic examination. In two nerves, there was a mild loss of myelinated axons; four had a moderate loss, and one, severe loss. Six of seven nerves showed predominantly axonopathic changes. In conclusion, (1) the prevalence rate of amyloid myopathy in muscle biopsy specimens was low (in this series, 0.004%); (2) only a minority of patients had multiple myeloma, and most presented with muscle weakness/fatigue or autonomic symptoms; (3) most of the muscles showed neurogenic features histologically; (4) all concomitant sural nerve biopsy specimens contained amyloid, and most showed a predominance of axonopathic changes.

Gelsolin-related familial amyloidosis, Finnish type (FAF), and its variants found worldwide.

Gelsolin-related familial amyloidosis, Finnish type, occurs worldwide, most likely as a result of sporadic low-frequency mutations. Two mutations at nucleotide 654 in the gelsolin gene have been demonstrated, which result in a characteristic triad of ophthalmologic, neurologic and dermatologic manifestations distinct from other amyloidoses. Some phenotypic variation, particularly in the age of onset and severity of manifestations, occurs but in general the disease is clinically rather homogeneous. Systemic deposition of amyloid is found in most tissues, predominantly in blood vessel walls and associated with basement membranes. The mutations result in amino acid substitutions with a charge change in the gelsolin molecule, postulated to alter the susceptibility for proteases thereby rendering the molecule amyloidogenic. Gelsolin fragments constitute the amyloid fibrils, but abnormal fragments also occur in patients' plasma and CSF providing evidence for the role of aberrant proteolysis in the disease pathomechanism. This is further strengthened by in vitro expression analyses showing both disease-related mutations to result in secretion of an abnormal gelsolin fragment, the likely precursor protein of gelsolin amyloid. Of the two forms of gelsolin, secretory and cytoplasmic, the secretory plasma form is the likely source of amyloid. The origin of the systemic amyloid deposits is not known but, beside a circulatory origin, local synthesis and deposition is an attractive pathomechanical alternative. The final goal of preventing or curing this disease has come closer, but still awaits further comprehensive pathological, functional and experimental studies in order to dissect all pathogenetically important events.

A pedigree analysis with minimised ascertainment bias shows anticipation in Met30-transthyretin related familial amyloid polyneuropathy.

In type I familial amyloid polyneuropathy (FAP) caused by a variant Met30-transthyretin (TTR), genetic anticipation has been reported. To determine whether anticipation of the disease is a true biological phenomenon or the result of ascertainment bias, we compared age at onset of the affected child with that of the affected parent in 68 parent-child pairs (including data on assumed age at onset and on asymptomatic obligate heterozygotes and parents at obligate 50% risk) in 15 families. Excluding the parent-child pairs involving the proband and "bilineal pairs", onset occurred earlier in the child than in the transmitting parent in 60 out of 68 "unilineal pairs". After correction for ascertainment bias resulting from incomplete penetrance and reduced biological fitness in early onset patients, the number of anticipation pairs (60 pairs) was still significantly larger than that of non-anticipation pairs (29.7 pairs) (p < 0.05). When the children were sons, the difference in age at onset was significantly greater in the mother-son pairs than in the father-son pairs (p = 0.023). Although not all ascertainment biases could be eliminated, these data show strong evidence that anticipation in the transmission of Met30-TTR FAP is a true biological phenomenon.

Late onset type I familial amyloidotic polyneuropathy: presentation of three autopsy cases in comparison with 19 autopsy cases of the ordinary type.

Clinicopathological features of three autopsy cases of extremely rare late onset type I familial amyloidotic polyneuropathy were presented and compared with 19 autopsy cases of the ordinary type. In the late onset cases, the ages at onset and at death were 27.5 and 24.5 years older, respectively, compared with the ordinary type. Also, duration of the total clinical course from onset to death was 3.7 years less than in the late onset cases. The degree of amyloid deposition was more marked in the heart of the late onset cases, causing prominent cardiac hypertrophy. It was also marked in the kidneys or thyroid of two cases, but slight to moderate in the peripheral or autonomic nervous tissues in all cases. Immunohistochemical investigation demonstrated the presence of transthyretin (TTR) as an amyloid precursor protein and of serum amyloid P-component in amyloid deposits in various organs and tissues of the late onset type. These findings, as well as serum levels of variant TTR, were similar to those of the ordinary type. These results suggest that there are some factors other than the amyloid precursor protein that effect the degree of amyloid deposition.

No association between apolipoprotein E epsilon4 allele and the age of onset in type I familial amyloid polyneuropathy.

It has been shown that the Apolipoprotein E (ApoE) epsilon4 allele increases the risk of developing Alzheimer's disease (AD) and lowers the age of its onset. ApoE has also been suggested to be a common facilitating factor in the different types of amyloidoses. However, the association of ApoE epsilon4 with the onset of disease in various types of amyloidoses has not been extensively investigated. Type I familial amyloid polyneuropathy (FAP) is one form of systemic amyloidosis in which ApoE co-localizes with amyloid deposits. We examined 54 patients with type I FAP and found that there was no significant effect of either ApoE epsilon2 or epsilon4 allele on the age at onset. Our results suggest that ApoE4 is not a facilitating factor in the development of FAP, transthyretin amyloidosis.