The first studies in the field of neuroscience began as early as the 19th
century in Geneva, before the installation of the Department of Psychiatry in its current location. The first important publications appeared in 1877 by Jean-Louis Prévost, who studied oculomotor functions and hemianopsy in hemiplegia.1
The earliest neuropathologic observations on postmortem brains in Geneva date from the last decade of the 19th
century. Dr Joannès Martin, the head of the “Asile des Vernets,” as the hospital for the insane was then known, and his assistant, Dr Jean Pilz, prepared the first histological slides from brain autopsies. Paul-Louis Ladame, privat-docent
at the University of Geneva in neuropathology, studied mainly general paresis,2, 3
and Huntington’s disease.5
These were the first steps to the extended neuropathological and clinicopathological studies that were continued into the 20th
century until today.
The new site of the psychiatry hospital called “Asile de Bel-Air” opened on November 9th
1900, and Professor Rodolphe Weber, the first director of the psychiatric hospital also inaugurated the “Laboratory of neuropathology for anatomohistological studies of the brain.” In these days, autopsies were performed by medical doctors and psychiatrists. The first certified neuropathologist was hired only in 1947.6
From these first decades of the 20th
century, works originated on the aphasias,7, 8
and vascular and neoplastic encephalopathies.11-15
Also from the beginning of the 20th
century dates the collection of histological slides (the oldest one from 1901, the case of an enormous meningioma was published in 1905;11
), and brain tissues embedded in paraffin blocks—of which more than 100,000 have been collected until today.
(a) The oldest histological slide of the collection dates from 1901: it is an enormous meningioma of the orbitofrontal region. (b) The case was published in the Nouvelle Iconographie de la Salpêtrière in 1905.
In the first years, autopsies were performed only occasionally, in what were considered medically “interesting” cases. Later (around 1920), on the initiative of Professor Charles Ladame, an autopsy was systematically requested for any patient who died in the hospital. Charles Ladame was first hired as an assistant by Rodolphe Weber. He performed extensive histological studies on brains of mentally affected patients and published the summary of his medical thesis in 1909 in the then-prominent French medical journal, L’Encéphale.16
He described the histological lesions seen in syphilitic encephalopathy (granular ependymitis and rod-shaped microglia),17, 18
in vascular dementia (arteriolar hyalinosis),19, 20
revisited briefly the structure of senile plaques (foyers de sclérose miliaire
, military sclerosis foci), and neurofibrillary tangles (scléroses neuronales
, neuronal sclerosis)16
—two years after Alzheimer’s original description.
In 1925, Charles Ladame replaced Rodolphe Weber as head of the psychiatric hospital and hired Ferdinand Morel as assistant in 1927. With Morel, an important period of the research in the field of dementia began. Morel was primarily interested in histological lesions in cases with dementia—principally, in senile dementia or late-onset Alzheimer’s disease. In addition to a great amount of research activity, he established a laboratory for research and postmortem neuropathological diagnosis (named Encéphale
). Morel said that to obtain new knowledge, the only valid method was to use the “anatomo-clinical” method, as had been done in earlier years in cases of Alzheimer’s or Pick’s diseases.21
Morel was the first to perform silver impregnations (Bielschowsky and del Rió Hortega techniques) on brain tissues in this laboratory. Owing to his observations and descriptions of lesions, his name became internationally known, and two pathologies bear his name today: the Morgagni-Morel syndrome (hyperostosis frontalis interna, obesity, and virilization-hirsutism—in which he also described the associated menstrual disturbances)22
and the laminar sclerosis of Morel (seen in alcoholic dementia as a gliosis in layer III of the frontal cortex).23
In 1938, Morel became head of the Department of Psychiatry. In 1943, he published—after Oppenheim, Bielchowsky, and Löwenberg at the beginning in the 20th
century—the third case of dyshoric angiopathy (drüsige Entartung
or angiopathie topistique
; Figs. and ),24
one of the secondary histopathological signs of Alzheimer’s disease, seen most often in layer IVc of Brodmann area 17. It was Morel who first related this lesion to Alzheimer’s disease. Some years later, Morel, with Erwin Wildi, presented a series of 43 cases with dyshoric angiopathy.25
They concluded that dyshoric angiopathy is seen only in the presence of senile plaques and is accompanied often by hyperproteinemia, and they postulated that dyshoric angiopathy is due to increased permeability of cortical capillaries.
Morel’s first publication on dyshoric angiopathy (a) and Pantelakis’ article on congophilic angiopathy (b).
Figure 3 Dyshoric angiopathy. (a) Thioflavin fluorescence, (b–e) modified Gallyas silver impregnation. Scale bar: (a) 200 μm, (b) 100 μm, (c–e) 50 μ.
Among Morel and Wildi’s collaborators, Stefanos Pantelakis published a study on 26 cases of another form of angiopathy, called congophilic angiopathy26
(). In contrast to dyshoric angiopathy, meningeal and perforant arteries are also affected. Today, these lesions together are referred to as amyloid angiopathy.
The microscopic research with Wildi on the aging brain continued with studies of granular atrophy,27
an ischemic lesion corresponding to cortical scars (Figs. and ). Wildi also published on histopathologic changes in aged patients with schizophrenia.28
Severe granular atrophy of Morel in the parieto-temporo-occipital region.
Histological picture of multiples cortical microinfarcts in the frontal cortex (black arrows). Inset: Neoformation of microvessels around the necrotic area (white arrow). Globus silver impregnation. Scale bar: (a) 500 μm, (b) 200 μm.
In 1959, Julian de Ajuriaguerra succeeded Morel as chair of Psychiatry. He is known as an important personality in the modernization and liberalization of psychiatry. Under his influence, Jean Constantinidis, engaged originally by Morel, pursued ongoing work in neurodegenerative disorders. One of Constantinidis’ important contributions was a new neuropathological classification of Pick’s disease into three types (A, B, and C), depending on the presence or absence of Pick’s bodies and ballooned neurons; this system was widely used until it was replaced by the recent classification of frontotemporal dementias, of which it was truly a forerunner29
and is still frequently cited today (). Additionally, Constantinidis continued Morel’s clinicopathological studies of Alzheimer’s disease and, in 1964, introduced histochemical methods in his laboratory to examine the distribution of monoamines in the brain using histofluorescence.30
Asymmetrical brain atrophy of both temporal lobes in Pick’s disease (Loyez staining) (a). Constantinidis’ paper on a new classification of Pick’s disease (b).
Research on neuropeptides followed work investigating monoaminergic systems.31, 32
The production of antibodies against various neuropeptides allowed the Bel-Air team to perform detailed cartographies of substance P, Leu- and Met-enkephalins, somatostatin, vasoactive intestinal peptide, cholecystokinin,33-37
delta sleep-inducing peptide (DSIP), corticotropin-like intermediate lobe peptide (CLIP), and orexin,38-42,43
together with studies of the implications of these neuropeptides in human pathology.37, 44