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Happy 20th anniversary, Neurodegenerative Diseases! The research in the field of neurodegenerative diseases has shown a remarkable growth and expansion during these last 20 years, especially in terms of therapeutical approaches. Interestingly, the first 20 years of the 21st century have some fascinating parallels with the first 20 years of the 20th century.

During the beginning of the 20th century, the major neuropathological descriptions of the neurodegenerative diseases have been identified. In 1906, Alois Alzheimer presented “A peculiar severe disease process of the cerebral cortex” at the 37th Meeting of South-West German Psychiatrists in Tübingen – the pathological description of the combination of senile plaques and neurofibrillary tangles from the brain of Auguste Deter: a 55-year-old woman who died after being admitted at the Frankfurt Asylum at the age of 51 years for aphasia, amnesia, anxiety, and sometimes violent behavior [1]. Few years later, in 1910, Emil Kreapelin used the term Alzheimer’s disease in Chapter 7 “Senile and Presenile Dementia” in the 8th Edition of “Clinical Psychiatry: A Textbook for Students and Doctors” to refer to the description of few cases from Alois Alzheimer [2].

At the same time, Arnold Pick was describing a few cases of demented patients with localized atrophy. He reported the case of August H, representing the first historical description of a primary progressive aphasia with an autopsy revealing a pronounced left temporal atrophy [3, 4]. Pick’s objective was to demonstrate the existence of a “focal” neurodegenerative condition. Few years later, Pick published the case of Anna H. presenting with progressive behavioral disturbances without memory or language deficits [5]. This description was more likely due to a behavioral variant of frontotemporal dementia, as suggested by Snowden in 1996 [6]. Ironically, what we called later Pick bodies was not described by Arnold Pick, but by Alzheimer [7] in 1911. During the 20th century, the usage of Pick’s disease was either devoted to clinical diagnosis of frontotemporal dementia or to neuropathological findings of Pick bodies.

Similar is the history of Frederich Lewy, another major game player in the field of neurodegenerative diseases. In 1912, Frederich Lewy, while studying the brain of 25 patients with Parkinson’s disease in the same laboratory of Alois Alzheimer at the Royal Psychiatric Clinic in Munich, described for the first time the characteristic eosinophilic inclusions in subcortical regions (notably not in the substantia nigra) – which is known today as “corps de Lewy” or “Lewy bodies” [8]. It was only in 1997 that the composition of Lewy bodies was elucidated as an aggregation of alpha-synuclein filaments [9]. Lewy died in October 1950 in Pennsylvania, without knowing the immense extent of his discoveries, especially without knowing that the second most frequent neurodegenerative dementia would be named after him. Like many other scientists of Jewish German origin, Lewy has been heavily affected by the Nazi regime. In 1932, he was dismissed from his position at the Charité Hospital in Berlin and forced to flee to London in 1933 to escape antisemitism [10]. Lewy was among the many scientists who attended Albert Einstein’s final speech at the Royal Albert Hall in London about the major threats for Jews in Germany [11] – a warning that was only fully understood few years later.

World War II impacted the scientific trajectory of the 20th century in many ways, and not only through the work of Jewish researchers living in countries occupied by the Nazi regime but also the Publishing House of our esteemed Journal Neurodegenerative Diseases. Karger Publishers was founded in Berlin in 1890 by Samuel Karger where a well-developed scientific milieu allowed for the growing success of Karger’s vision (Fig. 1). During the first years of the 20th century, his publishing business thrived and S. Karger’s tenacity kept the presses warm also amidst World War I. However, the circumstances in Germany that led to World War II became unsustainable. Following Samuel Karger’s death in 1935, Heinz Karger, his son, initiated plans to move out from Germany. With the help of friends, Heinz Karger successfully relocated, both the family business and his young family to Basel, Switzerland, escaping the Nazi regime in 1937 [12].

Fig. 1.

a First page of the 4th edition of the Book Lehrbuch der Nervenkrankheiten. Für Ärzte und Studierende by Prof. H. Oppenheim published in 1905. b Cover of Neurodegenerative Diseases as it appeared in 2005, showcasing the table of contents of the first issue of volume 2.

Fig. 1.

a First page of the 4th edition of the Book Lehrbuch der Nervenkrankheiten. Für Ärzte und Studierende by Prof. H. Oppenheim published in 1905. b Cover of Neurodegenerative Diseases as it appeared in 2005, showcasing the table of contents of the first issue of volume 2.

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While the early 20th century marked the major descriptions of the neuropathology of neurodegenerative diseases, the onset of the 21st century announces the treatment of these diseases. On November 29, 2022, after years of unsuccessful attempts, the New England Journal of Medicine published the positive results of the first anti-amyloid antibody, lecanemab, on reducing cognitive decline in patients with early Alzheimer’s disease [13]. This marked the beginning of a new era in the field of neurodegenerative diseases – the era of etiological therapy, prompting a reconsideration of the concept of Alzheimer’s disease and aging in general: the fatalism associated with the inexorable cognitive decline of Alzheimer’s disease needed to be reconsidered. Moreover, the gerontophobic principles stating that aging is linked to a slow and inevitable cognitive deterioration, for which exploring the cause is pointless, were no longer tenable. However, this enthusiasm was associated with significant clinical, ethical, economic, and societal questions. Indeed, the therapeutic class of anti-amyloid drugs “creates” new pathologies, the “Amyloid-Related Imaging Abnormalities” (ARIA), a complication characterized by cerebral edema with or without brain hemorrhage. This complication, whose pathophysiology is not fully understood, seems to be the consequence of a fragility of the blood-brain barrier that may cause an inflammatory reaction associated with the “clearance” of amyloid plaques by these antibodies. Although often asymptomatic, these ARIA can in certain rare situations lead to major lethal cerebral hemorrhages [14]. ARIA occur more frequently in certain profiles of Alzheimer’s disease, such as those carrying ApoE-4 alleles [15, 16], raising the crucial question of selecting the most favorable patients to minimize the risks of side effects. This question implies a comprehensive consideration of the magnitude of the clinical effect of these new treatments and, particularly, identifying which patients may be considered as good responders.

The frequency and severity of these side effects require close monitoring of patients, notably through the repetition of cerebral MRIs during the first year of treatment. However, this raises issues of cost and infrastructure and the question of healthcare systems’ capacity to treat these patients equitably. Indeed, some countries experience waiting times of over a year for consultations at Memory Centers. In Europe, the number of patients who could be considered for these treatments is estimated at 5.4 million, illustrating the need of major health system’s reorganizations [17].

If, for Alzheimer’s disease, this therapeutic revolution initiated by anti-amyloid treatments will more likely continue with therapies targeting the tau protein, other neurodegenerative diseases, such as frontotemporal lobar degeneration, will also benefit from treatments targeting their specific pathophysiology. This convergence of treatments targeting different pathophysiologies and reflecting the current trend toward so-called personalized medicine is particularly relevant in the context of aging, where patients often suffer from the coexistence of several neurodegenerative pathologies [18]. This intriguing parallel between the early years of the 20th and the 21st centuries in the field of neurodegenerative diseases holds the promise of signaling the end of the devastating impact of neurodegenerative diseases.

The author thanks Mrs. Teresa Mathews for reviewing the manuscript and providing insightful comments.

The author has no conflict of interest to declare.

This study was not supported by any sponsor or funder.

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