Alzheimer disease and cerebrovascular pathology: an update

Summary. Recent epidemiological and clinico-pathologic data suggest overlaps between Alzheimer disease (AD) and cerebrovascular lesions that may magnify the effect of mild AD pathology and promote progression of cognitive decline or even may precede neuronal damage and dementia.Vascular pathology in the aging brain and in AD includes: 1. cerebral amyloid angiopathy (CAA) with an incidence of 82–98% often associated with ApoEε2 and causing a) cerebral mass hemorrhages (around 70%, mainly in the frontal and parieal lobes), b) multiple or recurrent microhemorrhages (15%), and c) ischemic (micro-)infarcts or lacunes (around 20%). The frequency of these lesions increases with the severity of CAA and shows no correlation with that of senile amyloid plaques. CAA, significantly more frequent in patients with cerebral hemorrhages or infarcts than in aged controls, is an important risk factor for cerebrovascular lesions in AD. 2. Microvascular changes with decreased density and structural abnormalities causing regional metabolic and blood-brain barrier dysfunctions with ensuing neuronal damage. In large autopsy series of demented aged subjects, around 80% show Alzheimer type pathology, 20–40% with additional, often minor vascular lesions, 7–10% “pure” vascular dementia, and 3–5% “mixed” dementia (combination of AD and vascular encephalopathy). AD cases with additional minor cerebrovascular lesions have significantly more frequent histories of hypertension or infarcts than “pure” AD patients. Vascular lesions in AD include cortical microinfarcts, subcortial lacunes, white matter lesions / leukoencephalopathy, small hemorrhages and corticosubcortical infarcts, while in mixed type dementia multiple larger or hemispheral infarcts are more frequent. Small infarcts in AD patients have no essential impact on global cognitive decline which mainly depends on the severity of Alzheimer pathology, but in early stage of AD they may influence and promote the development of dementia. Recent studies showed lower density of plaques and tangles in brains with cerebrovascular lesions, and similar severity of dementia was related to fewer AD lesions in brains with than in those without small vascular lesions. Further studies will help to elucidate the risk factors and impact of cerebrovascular lesions on the development and progression of dementia in AD. Received November 2, 2001; accepted January 16, 2002     

Prevalence and impact of cerebrovascular pathology in Alzheimer's disease and parkinsonism

OBJECTIVE: To study the prevalence and impact of cerebrovascular lesions (CVL) in Alzheimer's disease (AD) and their effects on cognitive impairment. MATERIAL AND METHODS: In study I, the prevalence of vascular lesions in a prospective series of 244 autopsy-proved AD cases (mean age 83.1+/-8.4 years) and 230 age-matched non-demented controls was examined using immunochemistry and current morphological diagnostic criteria. In study II, in 100 consecutive autopsy cases (mean age 84.3+/-9.3 years), the incidence of general and capillary cerebral amyloid angiopathy (CAA, CapCAA) was examined. RESULTS: In study I, AD cases showed significantly more frequent CVL than age-matched controls without differences in the Braak stages, but the severity of CAA was significantly higher in AD brain with associated vascular lesions. In study II, CAA was more frequent in demented than in non-demented patients, but did neither correlate with high-grade AD pathology nor with clinical dementia, whereas CapCAA correlated with both dementia and high Braak stages; the severity of both types of CAA showed only low correlation with each other. CONCLUSIONS: The present data and other studies confirm the importance of CVL in AD and Parkinson's disease without considerable impact on cognitive impairment in progressed stages of AD, and the close association of CapCAA but not of general CAA with clinical dementia and AD pathology.     

Two distinct subgroups of senile dementia of Alzheimer type: Quantitative study of neurofibrillary tangles

The heterogeneity of senile dementia of Alzheimer type (SDAT) has been suggested by some authors clinically and neuropathologically. The heterogeneity of SDAT was investigated based on quantification of NFT combining Braak and Braak's neuropathological staging and the density of NFT in various areas of the cerebral cortex. Brain tissues were examined from 16 autopsy cases with clinically late onset dementia (>age 65) and neuropathologically diagnosed dementia of Alzheimer type (DAT). Gallyas–Braak staining was used for the quantification of NFT. The density of NFT was examined in the precentral gyrus, middle temporal gyrus (T2), parahippocampal gyrus and the amygdaloid nucleus. The 16 cases studied were divided into two groups depending on the number of NFT in the cortex (cut–off score: 5/mm²): the AD‐like group (NFT ≥ 5/mm²) and the common group (NFT < 5/mm²). The density of NFT in the precentral gyrus (t(3.225) = ?9.007, P = 0.002) and T2 (t(3.365) = ?3.774, P = 0.027) in the AD‐like group was significantly higher than those in the common group. However, no significant difference was observed in the parahippocampal gyrus between the two groups (t(14) = ?0.318, NS). Moreover, there were no significant differences between the two groups as regards age at onset and the duration of the illness. The present study revealed the possible existence of two subgroups in SDAT having significantly different NFT densities in various areas of the cerebral cortex without any significant difference in their duration of illness. This classification has no relationship to Braak and Braak's staging, which depends only on the distribution of NFT, irrespective of their density. Arai et al. revealed that the NFT density in AD was significantly higher than in SDAT. We suggest that the neuropathological findings of the AD‐like group in SDAT resemble those of presenile AD.     

Language patterns in Japanese patients with Alzheimer disease: A machine learning approach

Aim

The authors applied natural language processing and machine learning to explore the disease-related language patterns that warrant objective measures for assessing language ability in Japanese patients with Alzheimer disease (AD), while most previous studies have used large publicly available data sets in Euro-American languages.

Methods

The authors obtained 276 speech samples from 42 patients with AD and 52 healthy controls, aged 50 years or older. A natural language processing library for Python was used, spaCy, with an add-on library, GiNZA, which is a Japanese parser based on Universal Dependencies designed to facilitate multilingual parser development. The authors used eXtreme Gradient Boosting for our classification algorithm. Each unit of part-of-speech and dependency was tagged and counted to create features such as tag-frequency and tag-to-tag transition-frequency. Each feature's importance was computed during the 100-fold repeated random subsampling validation and averaged.

Results

The model resulted in an accuracy of 0.84 (SD = 0.06), and an area under the curve of 0.90 (SD = 0.03). Among the features that were important for such predictions, seven of the top 10 features were related to part-of-speech, while the remaining three were related to dependency. A box plot analysis demonstrated that the appearance rates of content words–related features were lower among the patients, whereas those with stagnation-related features were higher.

Conclusion

The current study demonstrated a promising level of accuracy for predicting AD and found the language patterns corresponding to the type of lexical-semantic decline known as ‘empty speech’, which is regarded as a characteristic of AD.     

Risk factors for dementia, depression and psychosis in long-standing Parkinson's disease

Summary. Objectives. To study the relationships between clinical features of Parkinson's disease (PD) and the development of dementia, depression or psychosis in patients with long-standing disease. Background. The natural history of dementia and depression in PD, and its relation to psychosis in long standing PD, are unclear. Method. 172 consecutive patients (99 men and 73 women, mean age at symptoms onset 58.3 ± 13.2 years) with 5 years or more of PD (mean symptom duration of 11.8 ± 5.6 years) were studied. Clinical data were collected during the last office visit through physical examination, detailed history, review of patient charts and outside documents. Dementia and depression were diagnosed according to DSM-IV criteria, while psychosis was diagnosed if hallucinations or delusions were present. Chi-square and t tests were used to compare the patient characteristics among those with vs. those without mental complications of the disease at different disease stages. Logistic regression was used for the comparison of associations between the presence of dementia or depression (dependent variable) and age at onset of PD, duration of PD and disease staging (explanatory variables). Results. The study population consisted of 45 patients at Hoehn & Yahr (H&Y) stage ≤2.5 (26%), 104 patients at stage 3 (60.5%) and 23 patients at H&Y stage 4–5 (13.5%). Sixty one patients (36%) had dementia, 55 patients had depression (33%) and 50 patients (27%) had psychosis. Dementia and depression were significantly associated with disease severity as reflected in the H&Y scale (P = 0.0003, Z = 3.59; P = 0.006, Z = 3.22, respectively). These associations were significant also for the older age of PD onset (≥59 years n = 89) subgroup (p = 0.001, Z = 3.2 for dementia and p = 0.02, Z = 2.9 for depression), but not for younger onset cases (<59 years n = 83). Dementia was significantly associated with older age of PD onset (β = 0.04, p = 0.009) while depression was inversely associated with age of PD onset (β = −0.04, p = 0.02). The presence of dementia was also significantly associated with depression (β = 1.49, p = 0.0006). Dementia and depression were found to be independent explanatory variables for the development of psychosis (logistic regression, odds ratio (OR) = 26.0, p < 0.0001; OR = 10.2, p < 0.0001, respectively). In patients with younger age of PD onset, depression more than dementia was strongly correlated with the appearance of psychosis. Conclusion. Dementia in PD was related to older age of symptoms onset and old age. Depression was associated with dementia or early age of PD onset. Depression seemed to contribute to the appearance of psychosis even more than dementia, especially in patients with younger age of symptoms onset. Received January 28, 1999; accepted June 30, 1999     

Parkinson's disease, smoking and family history

There is growing evidence that both genetic and environmental factors play a role in the etiology of Parkinson's disease (PD). The hypothesis of an interaction between genetic and environmental risk factors has been little explored, and never using a population-based case-control study design. Our objective was to investigate the possible interaction between smoking and family history in the etiology of PD, as a part of a collaborative population-based case-control study. We included 149 nondemented PD patients ascertained in three European prevalence surveys using a two-phase design. Each patient was matched by age (±2 years), gender, and center to three controls drawn from the same populations (n=375). Presence of PD among first-degree relatives and smoking history were assessed through an interview for 127 cased and 306 controls. In the overall sample we found suggestive evidence that family history and eversmoking interact in determining the risk of PD (P=0.09), with individuals exposed to both risk factors having the highest risk (OR=10.0; 95% CI=2.0–49.6). Analyses were repeated after stratification into two age-groups (cutoff: 75 years). In older patients, the joint exposure to both risk factors was associated with a significant increase in the risk of PD (OR=17.6; 95% CI=1.9–160.5). Among younger subjects, the OR for joint exposure was not significant. In conclusion, our findings suggest that smoking and family history interact synergistically on a multiplicative scale in determining the risk of PD in individuals older than 75 years. Received: 28 January 2000 / Received in revised form: 1 May 2000 / Accepted: 28 May 2000     

The natural history of dementia

This review summarizes studies on the natural history of dementia with a focus on Alzheimer's disease and vascular dementia. Understanding the course of dementia is important not only for patients, caregivers, and health professionals, but also for health policy‐makers, who have to plan for national resources needed in the management of an increasing number of dementia cases. From the available published data, the life expectancy of elderly people with dementia is shorter than that of non‐demented elderly. Reports on survival after a diagnosis of dementia vary from 3 to 12 years. The wide variation is partly due to the diagnostic criteria used in the studies and the sites where they were conducted (i.e. hospitals, clinics, or homes). There is an apparent difference in survival between Alzheimer's disease patients with onset of illness before 75 years and those after 75 years: the younger patients have a longer life expectancy. However, there are conflicting data on survival (in years) comparing male and female patients and comparing patients of different ethnicities. For vascular dementia, published papers on life expectancy vary between 3 to 5 years. Vascular dementia appears to have a poorer prognosis than Alzheimer's disease. The stages of severity of dementia were compared in a follow‐up of a sample of Alzheimer's disease patients in Singapore, and the mean duration of the mild phase (clinical dementia rating 1) was 5.6 years, the moderate phase (clinical dementia rating 2) was 3.5 years, and the severe phase (clinical dementia rating 3) was 3.2 years. At the various phases of the disease, the demand on health‐care services and economic cost are different.     

The urate and xanthine concentrations in the cerebrospinal fluid in patients with vascular dementia of the Binswanger type, Alzheimer type dementia, and Parkinson's disease

Summary We determined the urate and xanthine concentrations in the cerebrospinal fluid (CSF) in patients with vascular dementia of the Binswanger type (VDBT), Alzheimer type dementia (ATD), and Parkinson's disease (PD). We found that the urate concentration was significantly increased in VDBT patients, but significantly decreased in ATD patients compared with controls. The ratio of the concentrations of uric acid (U_CSF) to xanthine (X_CSF) in the CSF (U_CSF/X_CSF) had a significant correlation with the ratio of the U_CSF to the urate concentration in serum (U_serum) (U_CSF/U_serum) in ATD and PD, whereas U_CSF/U_serum increased independently of U_CSF/X_CSF in VDBT. We concluded that the significant increase in the urate concentration in VDBT is mainly due to an impairment of the blood-brain barrier (BBB), and its significant reduction in ATD may reflect impaired brain metabolism.     

A comparison of cerebral glucose metabolism in Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) share many similar aspects, and making a clinical diagnosis of one disorder over the other relies heavily on an arbitrary criterion, so-called 1-year rule. This study was designed to search for any difference of metabolic patterns in these two disorders using F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) images.
We enrolled 16 patients with PD, 13 patients with PDD, and seven patients with DLB. FDG PET was performed, and images were reconstructed by iterative reconstruction using the computed tomography (CT) images, and were normalized to a standard template. Statistical comparison between groups were performed on a voxel-by-voxel basis using t -statistics (two-sample t -test).
Compared with the patients with PD, both PDD and DLB patients showed similar patterns of decreased metabolism in bilateral inferior and medial frontal lobes, and right parietal lobe ( P _uncorrected < 0.001). In a direct comparison, DLB patients had significant metabolic decrease ( p _uncorrected < 0.005) in the anterior cingulate compared with those with PDD. These findings support the concept that PDD and DLB have similar underlying neurobiological characteristics, and that they can be regarded as a spectrum of Lewy body disorders.     

Dopaminergic contributions to the visual categorization of natural scenes: evidence from Parkinson's disease

Recent evidence raised the possibility that dopaminergic mechanisms in the neostriatum play an important role in categorization. In this study, we examined the electrophysiological correlates of natural scene categorization in Parkinson's disease (PD), which is characterized by the depletion of dopamine in the neostriatum. Event-related potentials (ERPs) were recorded in PD patients and age-matched control subjects using a natural scene categorization task. Subjects had to decide whether a briefly presented image contained animals or non-animals. In the control group, the mean amplitudes of N1 (150-250 ms) and N2 components (400-600 ms) were more negative for non-animal scenes as compared with stimuli containing animals, whereas P2 (250-350 ms) was more positive for animals. In contrast, in the PD group the mean amplitudes of N1 and N2 components were similar for both animal and non-animal stimuli, and the P2 amplitudes were reduced. In the case of N1 peak latency, there was no between-group difference, whereas the N2 and P2 components were significantly delayed in the PD group. These results suggest that both perceptual (N1) and semantic (N2) processes related to the categorization of natural scenes are specifically impaired in PD. In the temporal domain, the slowed semantic processing is preceded by a relatively normally paced perceptual analysis. These findings are in agreement with the hypothesis emphasizing the importance of striatal dopaminergic mechanisms in classification functions.     

The patients' perception of prodromal symptoms before the initial diagnosis of Parkinson's disease

Background:

Before the occurrence of motor symptoms permits the clinical diagnosis of Parkinson's disease (PD), about or even more than 50% of the dopaminergic neurons of the substantia nigra have degenerated. This time be called the prodromal phase of PD.

Objective:

To evaluate the time span from onset of first prodromal symptoms to the initial diagnosis of PD as well as the order of symptom occurrence.

Methods:

Retrospective study of 93 consecutively interviewed PD patients without dementia and 93 sex and age matched controls free of neurodegenerative disorders. A standardized in‐house telephone worksheet assessing 19 nonmotor and six early motor signs was used.

Results:

A total of 98.8% of all patients interviewed reported to have experienced prodromal symptoms prior to receiving the initial diagnosis of PD. Patients noticed an average of 7.6 different symptoms during this time interval. The mean time span between the recalled onset of any one symptom and PD diagnosis was 10.2 years. In both groups, the course of prodromal sign onset was associated with early neuropathological disease stages proposed by Braak.

Outlook:

These retrospectively gathered data confirm the existence of a long prodromal phase for PD that is consistent with neuropathological staging. A standardized questionnaire assessing such early symptoms may be helpful in identifying subjects at high risk for PD while they are still in the prodromal phase of the disorder. © 2011 Movement Disorder Society     

Differing patterns of psychiatric impairment in Alzheimer and demented parkinsonian patients

Psychiatric symptoms were investigated and compared in 95 patients with Alzheimer type dementia (DAT) and in 39 patients with Parkinson's disease with dementia (PD-D). The diagnosis of the dementia and psychiatric disorders was based on DSM III R criteria; dementia stage was assessed using the Clinical Dementia Rating Scale (CDR). PD-D were significantly older than DAT patients. Delirium was more frequent in the advanced stages of both PD-D and DAT, being mainly of the hypoactive type in PD-D and the hyperactive type in DAT. Delusions and hallucinations predominated in the early CDR stages of both illnesses and did not differ between groups; the same was true for depression. The results revealed different psychopathological profiles in DAT and PD-D patients.

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Sommario In questo studio sono stati valutati e confrontati i disturbi psichiatrici di 95 pazienti affetti da demenza a tipo Alzheimer (DAT) e di 39 parkinsoniani dementi (PD-D). La diagnosi di demenza e di disturbi psichiatrici è stata eseguita basandosi sui criteri del DSM III R, il livello di demenza è stato valutato secondo la Clinical Dementia Rating Scale (CDR). I PD-D erano significativamente più anziani dei DAT. Il delirium era significativamente più frequente negli stadi più avanzati, sia tra i PD-D che tra i DAT, manifestandosi prevalentemente come ipoattivo tra i PD-D, come iperattivo tra i DAT. I deliri e le allucinazioni predominavano ai livelli più bassi di CDR in entrambe le patologie, non differendo tra i due gruppi. Lo stesso avveniva per la depressione. I risultati hanno rivelato profili psicopatologici differenti nei PD-D e nei DAT.

     

Early stage memory impairment,visual hallucinations,and myoclonus combined with temporal lobe atrophy predict Alzheimer’s disease pathology in corticobasal syndrome

Corticobasal syndrome (CBS) is a typical phenotype of corticobasal degeneration (CBD). However, autopsy series have shown that many CBS cases emerge from various types of non-CBD pathology. We report a 73-year-old Korean man who was clinically diagnosed with CBS whose underlying pathology was Alzheimer’s disease (AD) at autopsy (CBS-AD). This case suggests that early developing memory impairment and myoclonus, severe temporoparietal atrophy, and visual hallucinations may support a more specific prediction of CBS-AD.     

Brain stem pathology in Parkinson's disease: An evaluation of the Braak staging model

The lower brain stem of 25 pathologically‐confirmed Parkinson's disease (PD) cases was examined by alpha synuclein immunohistochemistry to characterize pathological accumulation of alpha synuclein (Lewy‐type α‐synucleinopathy, LTS) in the medulla oblongata, to examine differences between affected regions and test a proposed model of staging of pathology in PD. All cases had LTS in the medulla, including the dorsal motor nucleus of the vagus (dmX), when present. The distribution followed a consistent pattern and appeared to be concentrated in a tyrosine hydroxylase (TH) immunoreactive region, probably representing the dorsal IX/X nuclear complex and the intermediate reticular zone. LTS density was greatest in the dmX. A similar distribution pattern to PD was seen in 14 incidental Lewy body disease (ILBD) cases, five derived from the Queen Square Brain Bank tissue collection and nine identified in separate series of 60 neurologically‐normal individuals, and in three cases with the G2019S mutation of LRRK2. Semiquantitative assessment showed that severity of pathology in the dmX was not correlated with the severity of cortical pathology. Semiquantitative assay of TH and ChAT peptide expression in the medulla showed that TH expression in PD and ILBD did not differ from controls. These findings broadly support the Braak hypothesis of caudo‐rostral development but indicate that the extent of the disease in the cortex and the severity of pathology in the medulla were independent of one another. © 2010 Movement Disorder Society     

Age at onset: the major determinant of outcome in Parkinson's disease

Factors at presentation which influenced the course of the disease and response to treatment were assessed in 125 de novo patients with Parkinson's disease. Ninety-eight patients were available for re-assessment at 5 years. Older patients presented earlier after the onset of symptoms, deteriorated more rapidly, and were significantly more likely to develop dementia and impairment of balance. Increasing age and symmetrical disease predicted the new appearance of imbalance. Age of onset did not predict dyskinesia or end of dose failure. A low tremor score at baseline and female gender were predictive of the early appearance of dyskinesia. Patients who experienced end of dose failure were taking a significantly higher dose of levodopa. Once dose and duration of treatment were corrected for, no baseline features were predictive of end of dose failure. The dose of levodopa at 5 years was positively correlated to baseline disease severity as measured by the Columbia score. We conclude that the age of onset of symptoms of Parkinson's disease is a major determinant of the course of the disease and response to treatment.     

The beneficial effect of cholinesterase inhibitors on patients suffering from Parkinson's disease and dementia

Summary. Patients suffering from Parkinson's disease (PD), often develop dementia (PDD). Their brain histology reveals Alzheimer's disease (AD) like changes and decreased cholin-acetyl transferase (ChAT) activity, in addition to typical PD changes. This cholinergic deficiency has been related to the degree of mental decline. As centrally acting cholinesterase inhibitors (ChEIs) provide cognitive and non-cognitive improvement for AD patients, the same therapeutic effect was hypothesized for PDD patients as well. The goal of this study was to assess the effect of ChEIs on both the cognitive and motor state of PDD patients. An open study was conducted. Eleven consecutive PDD patients (M/F 6/5 mean age 75 y) were found eligible for inclusion. They were treated for 26 weeks with tacrine (7 patients) and donepezil (4 patients) as add-on to their regular anti PD drugs. Cognitive assessment was performed at baseline and endpoint by Mini-Mental-State-Examination (MMSE) and Alzheimer's-Disease-Assessment-Scale (ADAS-cog). Global Deterioration Scale (GDS) was performed to evaluate active daily living (ADL). Motor evaluation was performed using Short Parkinson Evaluation Scale (SPES) at baseline and end-point. Statistical analysis used Student's paired t-test, ANOVA with repeated measures and Pearson correlation coefficient. ChEIs treated PDD patients showed improvement in their cognitive state. Mean ADAS-cog improved significantly by 3.2 points (p < 0.012). Mean MMSE and GDS improved non-significantly by 1.2 and 0.2 points respectively. There was no change in motor function as evident by mean SPES scores, 16.5 at baseline and endpoint. Five individuals actually demonstrated motor improvement under ChEIs. We conclude that ChEIs have a beneficial effect on the cognitive state of PDD patients without aggravating motor function. Received February 2, 2001; accepted June 27, 2001     

Cerebrospinal fluid norepinephrine, 3-methoxy-4-hydroxyphenylglycol and neuropeptide Y levels in Parkinson's disease, multiple system atrophy and dementia of the Alzheimer type

Summary Neuropeptide Y, one of the most abundant polypeptides within the nervous system, is co-stored with catecholamines, especially norepinephrine (NE), thus suggesting its possible involvement in pathologies characterized by a noradrenergic impairment. In Parkinson's disease (PD), as well as in multiple system atrophy (MSA), a central noradrenergic deficit has been demonstrated, and in the dementia of Alzheimer type (DAT) an impaired noradrenergic transmission has been postulated. In this study we determined CSF NE and MHPG levels in 29 PD, 15 MSA, 22 DAT patients and in 36 controls, while CSF NPY-immunoreactivity (NPY-ir) levels were measured in 10 PD, 7 MSA, 10 DAT patients and 20 controls. PD, MSA, and DAT patients showed a significant reduction in CSF NPY-ir and NE levels compared with controls, while CSF MHPG levels resulted in a reduction in only the MSA group.Furthermore, an inverse correlation between either NE or MHPG levels and the duration of the orthostatic hypotension was found in MSA patients while for DAT patients the MHPG levels were directly correlated to the severity of cognitive impairment, and inversely to the duration of illness.     

The dorsal raphe nucleus shows phospho‐tau neurofibrillary changes before the transentorhinal region in Alzheimer's disease. A precocious onset?

Aims:  Alzheimer's disease (AD) is a progressive and irreversible disease. There is strong evidence that the progression of the phospho-tau neurofibrillary cytoskeletal changes, rather than the β-amyloid burden, is crucial in determining the severity of the dementia in AD. The Braak and Braak staging system (BB) focuses mainly on the cortical cytoskeletal pathology and classifies this progressive pathology into six stages, spreading from the transentorhinal region to primary cortices. Although it is reported elsewhere that the midbrain's dorsal raphe nucleus (DR), which is connected with those areas of the cerebral cortex undergoing early changes during BB I and II, exhibits AD-related cytoskeletal pathology, this nucleus has not been considered by the BB. Methods:  To determine during which BB stage and how frequently the DR is affected by AD-related neurofibrillary changes, we studied the DR of 118 well-characterized individuals of the Brain Bank of the Brazilian Aging Brain Study Group categorized according to the BB. Thirty-eight of these individuals were staged as BB = 0, and 80 as BB ≥ 1. Results:  In all of the BB ≥ 1 individuals (cortical neurofibrillary changes were present at least in the transentorhinal region) and in more than 1/5 of the BB = 0 individuals neurofibrillary changes were detected in the supratrochlear subnucleus of the DR. Conclusions:  These observations: (i) support the hypothesis of transneuronal spread of neurofibrillary changes from the DR to its interconnected cortical brain areas; and (ii) indicate that the supratrochlear subnucleus of the DR is affected by neurofibrillary changes before the transentorhinal cortex during the disease process underlying AD.