In the era between Alzheimer's initial report in 1907 and 1960s, the primary focus of scholarship on dementia was the epistemology of the disease and the struggle for consensus on the clinical definitions (Dillmann 2000) Progress in understanding the relationships between the behavioral expression and pathological phenotypes of dementia was relatively slow during this period due to two impediments: first, the lack of objective clinical assessment tools, and second, uncertainty in the definition of the clinical phenomenon.
In the 1960s, arguably the start of the modern era of dementia research, clinical studies on dementia faced several challenges concerning the precise clinical characterization, definition and objective measures of the phenomena. Among these the most critical questions was 'whether Alzheimer changes were simply an accentuation of normal senescence'. The landmark investigations by the Blessed, Tomlinson and Roth in the mid-1960s (Blessed et al. 1968) began to address the challenge of distinguishing brain changes due to pathology from those alterations due to healthy aging were started in a number of. The studies by this group correlated quantitative measures of dementia (cognitive and functional impairments) with estimates of the number of the lesions (plaques), and the volume of brain destroyed by infarcts. The efforts to quantify the relationships between the clinical and biological indices of the disease established the foundation for later longitudinal studies (Blessed et al. 1968; Katzman 1976; Katzman, et al. 1978) However, the dispute could not be settled without comparisons of the clini-cal/biological/neuropathologicalphenotypes of the disease. Such comparisons became possible in the early 1960s with, the introduction of the electron microscope (EM) as a research tool, and the development of quantitative measures of dementia. [The answer to the long-standing problem of whether Alzheimer is an extension of aging was provided only recently by the findings of Jean-Jacques Haw and Charles Duyckaerts (Salpêtrière) that not all centenarians getAD].
In 1963, Terry (in the US) and Kidd (in the UK) independently reported the findings of EM studies showing the ultrastructure of a single neurofibrillary tangle to contain masses of microscopic fibers with periodic structure: paired helical filaments (PHF). These ground breaking studies enabled the field to: 1) develop quantitative assessments of the hallmark lesions, 2) clearly delineate the ultrastructure of the amyloid core (neuritic plaque), 3) develop methods of isolating plaques, neurofibrillary tangles and preparation of enriched PHFs, and 4) set the stage for the discovery of more sophisticated molecular and immunological probes to further characterize the abnormal proteins associated with the disease. Thus, these early ultrastructural studies by Terry, Kidd and colleagues opened the door for more detailed molecular characterization of the two fibrous proteins and set the stage for the remarkable advances of the last few years in understanding the molecular neurobiology of AD.
The second crucial hurdle that impeded progress in clinical studies in this period was the need for objective/quantitative tools to assess mental status for functional measures of severity. This problem was surmounted in 1968, with the publication of the Blessed, Tomlinson and Roth Dementia Scale (Information-Memory-Concentration Test). The instrument was an informant-based scale of memory function, orientation, information, concentration, activities of daily living, etc. The landmark prospective studies of this group for the first time correlated quantitative measures of dementia (cognitive and functional impairments) with estimates of the number of the lesions (plaques), and the volume of brain destroyed by infarcts. Although subsequently the validity of correlations has been questioned by Terry and others by arguing that loss of synapse is the more valid index of severity. Nevertheless, these early efforts to quantify the relationships between the clinical and biological indices of the disease established the foundation for subsequent program initiatives and several collaborative multi-site longitudinal studies launched by NIA.
In the mid-1960 to mid-1980 period, four categories of objective clinical measurement tools were developed and validated, some in longitudinal studies with autopsy confirmations. These include: Mental Status Exams (e.g., Dementia Scale or ICM Test-1968, Mini-Mental Status Exam -1975 (Folstein et al. 1975), Short Blessed Test -1983), Global Measures of Dementia Severity (e.g., Clinical Dementia Rating - 1993, Global Deterioration Scale - 1982, CAMDEX - 1986), Behavioral Scales (Geriatric Depression Scale - 1988, Agitation Inventory - 1986, CERAD Behavioral Rating Scale for Dementia - 1995, Clinical Impression of Global Change or CIBIC) and Cognitive Assessment Batteries (e.g., Alzheimer Disease Assessment Scale or ADAS-cog) (Rosen et al. 1984). The efforts to construct quantitative measures of cognition and the validation of instruments for objective evaluation of symptoms were critical to the refinements in the characterization of the disease. These advances in assessment of the severity of the disease became the foundation for much of the current "routine clinical-workup" and set the "standard" for clinical staging methods an essential element of clinical research.
The third clinical controversy, in the 1950s-1970s, revolved around the issue whether 'presenile' and 'senile' dementias were the same disorder. The lack of consensus on a clear "clinical" definition of the disease was an important hurdle for progress in clinical studies. The uncertainty about the true identity of Alzheimer's diseases lingered until the 1976 editorial by Katzman (Katzman 1976). This landmark paper was an important step towards the recognition a common cause for late-onset and pre-senile dementia, an earlier thesis suggested by Newton , and by Neuman and Cohn . This editorial for the first time framed Alzheimer's disease as a medical and public health issue. However, it did not speak to need for specific diagnostic criteria because in this period the DSM-III (DSM-IV) criteria for diagnosis of dementia seemed to be adequate most clinical work (Diagnostic and Statistical Manual of Mental Disorders. 1987). The needs for more rigorous clinical and neuropathological diagnostic criteria for research were addressed in the 1980s. The publication of the NINCDS-ADRDA diagnostic criteria in 1984 further specified three levels of confidence; probable, possible and definite with definite requiring histopathological confirmation (McKhann et al. 1984).
Once the challenges of developing diagnostic criteria and objective assessment instruments were overcome, the next major hurdle for clinical research was the effort to 1 ) validate the diagnostic criteria with histopathological confirmations; thus the need for neuopathological criteria, 2) standardize (reliability, sensitivity, specificity) various clinical assessment instruments and, 3) construct new measurements for changes in behaviors, symptoms or various domains ofcognition. The availability ofstandardized, well-validated quantitative assessment instruments were indispensable prerequisites for NIA's subsequent initiatives (Khachaturian 1985; Mirra et al. 1991; Braak and Braak 1991; Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. 1997. Consensus Report of the Work Group, 1998)
In order to expand research on diagnosis and treatments, in 1978 NIA began to promote the construction and validation of assessment tools specifically designed for cognitive changes in several different domains; i.e., the Alzheimer's Disease Assessment Scale (ADAS) in 1984. These early efforts were significantly facilitated by the establishment of three related clinical programs that provided necessary research infrastructure: [a) Alzheimer's Disease Centers (1984 b) Consortium to Establish Registries for Alzheimer's disease (CERAD) (1987)and, c) Alzheimer's Disease Cooperative Study (ADCS) (1991). Thus 1984 was a watershed year:
- NINCDS-ADRDA criteria provided a systematic clinical diagnostic system supporting comparisons across centers;
- Alzheimer Disease Research Centers were established;
- Glenner and Wong identified amyloid;
- Standardized cognitive assessment instruments and global measured of dementia severity were introduced (e.g., ADAS, CDR, CIBIC) and enabled multi-site collaborative clinical studies.
During the following two decades the improvements in the accuracy of the clinical diagnosis were remarkable. The procedures for clinical assessment steadily advanced towards well-validated algorithms for identification of positive clinical phenotypes of the diseases. Twenty years ago what would have been considered "mild" dementia now more likely would be staged as "moderate" dementia. Early diagnosis has become one of the most the important research and clinical accomplishments with profound implications for: establishing the prevalence of AD, initiating treatment when it may have optimal benefit, and understanding the pathobiology of the disease. For example, the original cholinergic hypothesis was based on neuropathologic material from endstage AD patients. Now that AD is diagnosed earlier, some investigators [e.g., Ken Davis and Steve DeKosky] have suggested that simple cholinergic hypofunction may not be a feature of the initial stages.
The introduction of mild cognitive impairment (MCI) as a potential precursor or prodrome of the disease (Petersen 2000) was another significant accomplishment. Several groups (e.g., Barry Reisberg, Steve Ferris and the NYU group, Thomas Crook formerly at NIMH, Ron Petersen and the Mayo Clinic group, Marilyn Albert and the MGH group, and John Morris and the Washington University group) contributed to the efforts to improve the definitions and algorithms for distinguishing the early stages from non-demented aging and in characterizing border zone conditions.
This work sets the stage for the exploration of biomarkers. Advances in molecular neurobiology and emerging imaging technologies promise to provide early markers of the asymptomatic stages. The classification of degenerative dementias is moving rapidly, not just toward diagnostic and prognostic biomarkers, but toward antecedent biomarkers; a system of categorization based on combined behavioral and protein abnormalities (e.g., amyloidopathy, tauopathies, synucleinopathies and prion protein disorders) (Cummings et al. 2003). The potential value of an amyloid imaging compounds [Pittsburgh Compound] for early diagnosis was recently demonstrated by Bill Klunk (Pittsburg), Henry Engler (Stockholm) and collaborators from Uppsala and Boston with their success in imaging Ap containing lesions in the living human brain with AD.
The prospects are promising that validated molecular and biochemical markers may soon complement clinical approaches in making early and valid diagnoses. However, prior to use as a routine clinical tool any potential biomarker must detect a fundamental biological feature of the disease and needs to be validated in neuropathologic confirmed cases. Presently none of the many [proposed] putative bio-markers have been validated in adequately powered investigations. Recent advances in neuroimag-ing technologies [e.g., Pittsburgh Compound with PET] offer the potential to detect and follow longitudinally the clinical course of the disease. In the future, it might be possible for neuroimaging technologies, perhaps MRI, to allow more direct monitoring of some biological phenotypes of the disease (e.g., brain metabolic changes, Ap, Tau, synapse loss or cell death via PET and other structural changes). In contrast to neu-ropsychological measurements, imaging measurements, when validated, could allow following the more proximal brain changes associated with disease progression.
Epidemiological studies of prevalence, incidence, selective risk factors and the interactions of genetic and epigenetic factors were critical to understanding the full clinical aspects of the disease. Epidemiological studies have provided some of the most important hypotheses concerning etiology and novel avenues for potential therapeutic strategies. One of the earliest contributions of epidemiological research was Ernest Gru-enberg's 1961 study showing the important relationship between age and prevalence of dementia; later confirmed by the East Boston study led by Dennis Evans indicating the exponential increase in the prevalence of dementia with age. Robert Katzman, a neurologist, shifted the focus of his research by becoming a neuro-epidemiologist to study the relationship between incidence of dementia and education. The possibility of a positive relationship between education, challenging occupations and dementia were confirmed by Richard Mayeux/Barry Gurland. An array of putative risk factors has been reported [e.g., culture-ethnicity (Hugh Hendie); ApoE-head trauma (Richard Mayeux);gender-ethnicity-ApoE(LinsdayFarrer); Rotterdam study on vascular factors-lifestyle-diabetes-dietary effects of antioxidants (Albert Hoffman, Monique Breteler); NSAID (Brietner); PAQUID study in Bordeaux reporting beneficial effect of wine (Jean-François Dartigues and Orgogozzo); description of an "Artic mutation", which leads to the production of lower level of Ap in plasma but enhanced protofibrill formation (Lannfeld)]. These findings have provided provocative and possibly useful new avenues for therapy development; however, none of these putative risk factors have been confirmed through prospective clinical trials; some which currently are underway.
In summary, these early struggles to define the disease made significant contributions to current clinical knowledge by laying the foundation for more recent efforts to: a) refine the clinical description of the phenomenon/symptoms, b) establish clinical - pathological correlations, c) develop objective measures of behavior - psychometric assessment instrument, d) establish diagnostic criteria, e) standardize diagnostic procedures, f) refine clinical assessment algorithms, g) develop validated screening instruments and/or biological markers for early detection of mild cognitive changes and h) establish infrastructures for longitudinal clinical-pathological studies. Perhaps the most significant factor for the subsequent successes of the field was the integration and parallel developments in defining both the behavioral and biological phenotypes of the disease. The cross-talk and interdependent advances in basic and clinical studies was a unique and important part of the story.
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