Familial frontotemporal dementia: a report of three cases of severe cerebral atrophy with rare inclusions that are negative for tau and synuclein,but positive for ubiquitin

We describe the brain autopsy findings from three of five siblings who suffered dementia with clinical diagnoses including Alzheimers, Parkinsons, and Picks disease. Five other living siblings appear unaffected. All of the autopsied brains showed severe atrophy (brain weights 613, 641, and 750 g) of the frontal and temporal lobes, and to a slightly lesser extent of the parietal lobes, while the occipital lobes were relatively preserved. The substantia nigra showed marked neuronal loss with gliosis. No ballooned neurons, neurofibrillary tangles, neuritic plaques, Pick bodies, or Lewy bodies were found in these brains. Immunohistochemistry for tau protein failed to reveal neuronal or glial inclusions, and normal tau protein was found in a separate Western blot study [Adamec et al. (2001) Neurosci Lett 315:21–24]. Rare neurons with ubiquitinated cytoplasmic inclusions were scattered in the neocortex and hippocampus. The overall pathological features were consistent with a severe form of frontotemporal dementia (FTD) with involvement of the substantia nigra. Whether the rare ubiquitinated inclusions are sufficient to classify these cases as FTD with motor neuron disease type inclusions but without motor neuron disease, or FTD dementia lacking distinctive histological features remains unclear. The features of lobar circumscribed atrophy without Pick bodies and without ballooned neurons, however, are consistent with Pick disease group C in the Constantinidis classification [Constantinidis et al. (1974) Eur Neurol 11:208–217].     

Two distinct ubiquitin immunoreactive senile plaques in Alzheimer's disease: relationship with the intellectual status in 29 cases

Summary The aim of this study was the analysis of the development of neurofibrillary tangles (NFT) and senile plaques (SP) during aging and senile dementia of the Alzheimer type. The lesions stained by ubiquitin, tau and A4 antibodies were studied in Brodmann's area 22 (superior temporal gyrus) in 29 cases. Samples were from a group of women over 75 years of age, psychometrically assessed and either normal or affected by Alzheimer's disease at various degrees of severity. NFT were less numerous when revealed by ubiquitin than by tau antibodies, suggesting that ubiquitin immunoreactivity appeared later in the course of the disease. Ubiquitin immunoreactive (IR) SP were made of clusters of IR neurites usually organized around a central amyloid core. Two types of ubiquitin-IR SP were designated. Globular neurite SP contained weakly immunostained globular neurites. They were densest in the least affected cases. However, they were not seen in every normal or lightly affected case, and were always present in the most affected ones. The density of these globular neurite SP was not significantly correlated with the severity of dementia, nor with the density of the lesions stained by tau antibodies (neuritic component of SP, NFT and neuropil threads) or by A4 antibodies (diffuse or dense deposits). The curly neurite type of SP contained curly neurites strongly immunostained by ubiquitin antibodies. They exhibited the highest density in the most affected cases, where they were always present. They were lacking in the least affected cases. They were always found together with the globular neurite SP. The density of these curly neurite SP was significantly correlated with the severity of dementia, and with the density of tau-IR lesions and dense amyloid A4 deposits. It was not correlated, however, with the density of diffuse A4 deposits. Our results suggest that the globular neurite SP and the curly neurite SP were not systematically linked. Ubiquitin immunoreactivity in the globular neurite SP could be a transient event in the course of the disease and in the formation of SP. On the contrary, ubiquitin immunoreactivity in the curly neurite SP and NFT seemed to appear after tau immunoreactivity. These ubiquitin conjugates could constitute an irreversible lesion related to dementia.Supported in part by a grant from the Association France Alzheimer and the Caisse de Retraite et de Prévoyance Haussmann (to P.D.)     

Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and α-synuclein pathology

Alzheimers disease (AD), Picks disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or -synuclein. In AD, -amyloid (A)-associated caspase activation and cleavage of tau at Asp⁴²¹ (Tau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether Tau accumulates in other diseases not characterized by extracellular A accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied Tau accumulation in DLB cases associated with intracellular -synuclein. Tau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of Tau may represent a common pathway associated with abnormal accumulation of intracellular tau or -synuclein and may be relatively less dependent on the extracellular accumulation of A in non-AD dementias.     

Immunoreactivities of amyloid β peptide<Subscript>(1–42)</Subscript> and total τ protein in lumbar cerebrospinal fluid of patients with normal pressure hydrocephalus

Summary. Immunoreactivities of amyloid peptide_(1–42) (A42-IR) and total protein (TTIR) were measured in lumbar cerebrospinal fluid of 48 patients (12 patients in each group) with normal pressure hydrocephalus (NPH), vascular dementia (VD), Alzheimers disease (AD), Parkinsons disease without dementia (PD) and 24 controls (CON) using sensitive and specific enzyme immunoassays. TTIR in NPH was not significantly changed compared with VD, PD and CON, while NPH-A42-IR was significantly decreased compared with PD and CON. In AD, significant increases of TTIR and significant decreases of A42-IR were found. Using a TTIR by A42 plot, all NPH, PD, and CON samples were within the non-AD plot region. 92% of AD and VD samples were within the AD and non-AD area, respectively. We conclude that combined measurement of A42-IR and TTIR contributes to the differential diagnosis of NPH vs. AD and of AD vs. VD, respectively.     

Metabolic/signal transduction hypothesis of Alzheimer’s disease and other tauopathies

Alzheimers disease (AD), the major cause of dementia in middle- to old-aged individuals, is multifactorial. Independent of the etiology, whether genetic or non-genetic, this disease is characterized by extracellular -amyloid plaques and intraneuronal neurofibrillary tangles of abnormally hyperphosphorylated tau. However, the molecular mechanisms of neither AD nor other tauopathies are completely understood. To date, the most popular hypothesis of AD is the Amyloid cascade hypothesis, according to which -amyloid, the cleavage product of -amyloid precursor protein (APP), is neurotoxic and causes neurodegeneration and dementia. However, this hypothesis is inconsistent with the presence in normal aged human brain of the -amyloid plaque burden similar to that in AD, and the absence of neurofibrillary pathology and neurodegeneration in mutated APP, presenilin-1 and presenilin-2 transgenic mice that show extensive -amyloid plaque pathology. Here we propose an alternate hypothesis, the Metabolic/signal transduction hypothesis, which is consistent both with the pathology seen in AD and other tauopathies and as well as all experimental animal conditions. In this hypothesis, with increasing age, the fluidity of neuronal membranes is progressively reduced, which makes it less resistant to environmental/metabolic insults affecting one or more signal transduction pathways, which lead to a protein phosphorylation/dephosphorylation imbalance and abnormal hyperphosphorylation of tau. The hyperphosphorylated tau sequesters normal tau, MAP1 and MAP2, which results in breakdown of the microtubule network and, consequently, a progressive retrograde degeneration of the affected neurons and, ultimately, dementia.     

Are VEP abnormalities in optic neuritis (ON) dependent on plaque size? A reappraisal of the physiopathology of ON based on improved MRI and multiple-lead recordings

Twenty patients with optic neuritis (ON) described in the previous study [23] underwent serial VEP recordings (using multiple electrode arrays) for two years. The VEPs could be correlated with the lesions revealed by MRI, Visual Field tests and other clinical findings. On the basis of their scalp distribution, they were classified as really delayed VEPs and pseudo-delayed VEPs.Real delays could be recorded at the onset of ON or shortly afterwards, and their appearance indicated the recovery of visual function and a good prognosis.Pseudo-delays indicated an alteration in the visual field and, unless a breakthrough of normal or delayed components appeared in the first three months, following acute ON, indicate a poor prognosis for the recovery of visual function.The pseudo-delayed VEPs were mainly observed in patients with longer lesions revealed by means of LTE-STIR MRI [23]; there was no correlation between VEP latency and the length of plaques.Our findings contradict previous theories on the timing of conduction alterations in ON and multiple sclerosis.

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Sommario I 20 pazienti affetti da Neurite Ottica (NO), descritti nel precedente lavoro [23] sono stati sottoposti a registrazioni seriali multicanali dei Potenziali Evocati Visivi (PEV), per un periodo di 2 anni dall'esordio della NO. I PEV potevano correlare con le lesioni evidenziate con la Risonanza Magnetica, con le alterazioni campimetriche e con altri reperti clinici. Basandoci sulla loro distribuzione in mappa, i PEV sono stati classificati come realmente ritardati e pseudo-ritardati. PEV realmente ritardati potevano essere registrati all'esordio, o precocemente dopo l'episodio di NO, e la presenza del ritardo stava ad indicare un recupero della funzione visiva e, quindi, una prognosi fausta.Gli pseudo-ritardi indicavano un'alterazione del campo visivo a prognosi non favorevole per un recupero della funzione visiva, a meno che entro i primi 3 mesi dalla NO si fosse verificata una ricomparsa di componenti normali o ritardate.Gli pseudo-ritardi erano rilievi caratteristici nei pazienti con lesioni maggiormente lunghe alle immagini LTE-STIR MRI [23]. Nessuna correlazione è stata trovata tra latenza dei PEV e lunghezza delle placche.I nostri rilievi sono in disaccordo con precedenti teorie relative ai tempi di instaurazione-recupero delle alterazioni di conduzione nella NO e nella Sclerosi Multipla.

     

Intelligence and temperament as protective factors for mental health. A cross-sectional and prospective epidemiological study

The Sjöbring system of personality dimensions measuring intellectual capacity, activity, impulsivity and sociability was used to study possible salutogenic (i.e. causes of health) effects. The study comprised 590 subjects investigated in 1947, 1957, 1972 and 1988–1989 in the Lundby project, an epidemiological study in Sweden. Psychiatric diagnoses were made in 1947, 1957 and 1972. Mental health was estimated in 1988–1989 using the concept love well, work well, play well and expect well. The Sjöbring dimensions were clinically assessed in 1972. Both in the concurrent study in 1972 and in the prospective study in 1988–1989 super capacity (high intellectual function), super validity (high activity level) and super solidity (low impulsivity) were statistically associated with lower frequencies of certain psychiatric diagnoses and a higher frequency of positive mental health. These variables are proposed to increase coping capacity, and therefore increase stress resilience.     

αB-Crystallin is present in reactive glia in Creutzfeldt-Jakob disease

Summary -Crystallin is a major eye lens protein, composed of two types of subunits, A and B. The A subunit is restricted to the lens, but B-crystallin has recently also been detected in non-lenticular tissues, including the nervous system. With the use of a polyclonal antiserum directed against a synthetic C-terminal peptide of human B-crystallin, the presence of B-crystallin could be demonstrated immunohistochemically in astrocytes in the brains of patients with Creutzfeldt-Jakob disease (CJD). Most intensive localization was observed in the spongiotic tissue representing abundant progressively changed astrocytes in CJD. In agematched control brains weak positive reaction was located in individual oligodendroglia cells and subpial astrocytes. Prominent increase of B-crystallin in pathological glia in CJD may represent a response to stress.     

Ultrastructure of peripheral nerve in metachromatic leucodystrophy

Summary An electron microscopical study of two consecutive nerve biopsies from a patient with metachromatic leucodystrophy (sulphatide lipidosis) was made. The ultrastructural changes observed consisted of: a) irregular whorls of myelin. The myelin in the whorls showed a thickened, sometimes doubled, intraperiod line, which was barely visible in compact myelin; b) inclusion bodies up to 1 in diameter in the cytoplasm of Schwann cells. These had a lamellar structure, with stacked membranes 60 Å apart; c) a loose pattern of the myelin in some nerve fibers, with loss of the intraperiod line, and d) presence of abnormally dense mitochondria with thickened cristae in Schwann cells. It is suggested that: a) the whorl formation and the ultrastructural abnormalities of the myelin in the whorls may be due to impaired myelin synthesis, and b) that the inclusion bodies may represent the accumulation of cerebroside sulfate in micellar aggregates. The loose pattern of myelin is considered artifactural until proven otherwise.

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Zusammenfassung Zwei aufeinanderfolgende Nervenbiopsien bei einem Patienten mit metachromatischer Leukodystrophie (Sulfatid-Lipoidose) wurden elektronenoptisch untersucht. Die beobachteten ultrastrukturellen Veränderungen bestehen in: a) unregelmäßigen Wirbelbildungen (whorls), in welchen das Myelin Verdickungen, manchmal Verdopplung des Zwischenstreifens (intraperiod line) aufweist, was im kompakten Myelin kaum sichtbar ist. b) Einschlußkörperchen mit einem Durchmesser bis zu1 im Cytoplasma der Schwann-Zellen. Diese weisen lamelläre Struktur mit einem Membranabstand von 60 Å auf. c) ein lockeres (loose) Myelinmuster mit Verlust des Zwischenstreifens in einigen Nervenfasern und d) Auftreten von abnorm dichten Mitochondrien mit verdicktem Cristae in Schwann-Zellen. Es wird angenommen, daß a) die Wirbelbildungen und die ultrastrukturellen Myelinabnormitäten in den Wirbeln einer gestörten Myelinsynthese entsprechen und b) daß die Einschlußkörperchen die Anhäufung von Cerebrosidsulfat in micellaren Verbänden darstellen. Das lockere Myelinmuster wird vorläufig als artifiziell angesehen.

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This investigation was supported in part by Public Health Service Research Grant No. FR-86 from the N.I.H. Division of Research Facilities and Resources.     

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.